Oxazolyl-arylproplonic acid derivatives and their use as ppar agonists

ABSTRACT

Compounds represented by the following structural formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: n is 2, 3, or 4 and W is CH 2 , CH(OH), C(O) or O; R1 is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl-alkyl, or t-butyl; R2 is H, alkyl, haloalkyl or phenyl; Y is an unsubstituted or substituted thiophen-2,5-diyl or phenylene; R3 is alkyl or haloalkyl; R4 is a substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl, pyridyl or benzo[1,3]dioxol-5-yl group; and R5 is H, alkyl, or aminoalkyl; are useful for modulating a peroxisome proliferator activated receptor, particularly in the treatment of diabetes mellitus.

This is the national stage application under 35 USC 371 forPCT/US01/22616, filed Aug. 23, 2001, which claims the benefit of U.S.Provisional Application Ser. No. 60/227,234, filed Aug. 23, 2000.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include PPARα, PPARβ or NUC1, PPARγand PPARδ.

The PPARα receptor subtypes are reported to be activated by medium andlong-chain fatty acids. They are involved in stimulating beta-oxidationof fatty acids and with the activity of fibrates which reportedlyproduce a substantial reduction in plasma triglycerides and moderatereduction in low density lipoprotein (LDL) cholesterol. The PPARγreceptor subtypes are reportedly involved in activating the program ofadipocyte differentiation and are not involved in stimulating peroxisomeproliferation in the liver.

Diabetes is a disease in which a mammal's ability to regulate glucoselevels in the blood is impaired because the mammal has a reduced abilityto convert glucose to glycogen for storage in muscle and liver cells. InType I diabetes, this reduced ability to store glucose is caused byreduced insulin production. “Type II Diabetes” or “non-insulin dependentdiabetes mellitus” (NIDDM) is the form of diabetes which is due to aprofound resistance to insulin stimulating or regulatory effect onglucose and lipid metabolism in the main insulin-sensitive tissues,muscle, liver and adipose tissue. This resistance to insulinresponsiveness results in insufficient insulin activation of glucoseuptake, oxidation and storage in muscle and inadequate insulinrepression of lipolysis in adipose tissue and of glucose production andsecretion in liver. When these cells become desensitized to insulin, thebody tries to compensate by producing abnormally high levels of insulinand hyperinsulemia results. Hyperinsulemia is associated withhypertension and elevated body weight. Since insulin is involved inpromoting the cellular uptake of glucose, amino acids and triglyceridesfrom the blood by insulin sensitive cells, insulin insensitivity canresult in elevated levels of triglycerides and LDL which are riskfactors in cardiovascular diseases. The constellation of symptoms whichincludes hyperinsulemia combined with hypertension, elevated bodyweight, elevated triglycerides and elevated LDL is known as Syndrome X.

Current treatment for diabetes mellitus generally first involvestreatment with diet and exercise. However, compliance can be poor and asthe disease progresses treatment with hypoglycemics, typicallysulfonylureas, is often necessary. Sulfonylureas stimulate the β cellsof the liver to secrete more insulin. However, the response of the βcells eventually fails and treatment with insulin injection isnecessary. In addition, both sulfonylurea treatment and insulininjection have the life threatening side effect of hypoglycemic coma.Therefore, patients using these treatments must carefully controldosage.

Thiazolidinediones are a class of compounds which have been shown toincrease the sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. Thiazolidinediones have been shown toincrease insulin sensitivity by binding to PPARγ receptors. However,side effects associated with treatment with thiazolidinediones includeweight gain, and, for troglitazone, liver toxicity.

PPARα and PPARγ receptors have been implicated in diabetes mellitus,cardiovascular disease, obesity, and gastrointestinal disease, such as,inflammatory bowel disease. There exists a need for new pharmaceuticalagents which modulate these receptors to prevent, treat and/or alleviatethese diseases or conditions while ameliorating side effects of currenttreatments.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by StructuralFormula I and pharmaceutically acceptable salts, solvates and hydratesthereof:

In Structural Formula I, n is 2, 3, or 4 and W is CH₂, CH(OH), C(O) or0. R1 is an unsubstituted or substituted group selected from aryl,heteroaryl, cycloalkyl, heterocycloalkyl, aryl-C1-C4 alkyl,heteroaryl-C1-C4 alkyl, cycloalkyl-C1-C4 alkyl, or t-butyl. R2 is H,C1-C4 alkyl, C1-C4 haloalkyl or phenyl. Y is an unsubstituted orsubstituted group consisting of thiophen-2,5-diyl or phenylene. R3 isC1-C4 alkyl or C1-C4 haloalkyl. R4 is a substituted or unsubstitutedphenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl, pyridyl orbenzo[1,3]dioxol-5-yl group. R5 is H, C1-C4 alkyl, or aminoalkyl.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofmodulating a peroxisome proliferator activated receptor by contactingthe receptor with at least one compound represented by StructuralFormula I, and pharmaceutically acceptable salts, solvates and hydratesthereof.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention and pharmaceutically acceptablesalts, solvates and hydrates thereof are believed to be effective intreating Syndrome X, Type II diabetes, hyperglycemia, hyperlipidemia,obesity, coagaulopathy, hypertension, atherosclerosis, and otherdisorders related to Syndrome X and cardiovascular diseases because theylower one or more of the following in mammals: glucose, insulin,triglycerides, fatty acids and/or cholesterol. In addition, thecompounds exhibit fewer side effects than compounds currently used totreat these conditions.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, alkyl groups include straight chained or branched C1-C4hydrocarbons, which are completely saturated.

Cycloalkyl groups, as used herein, include C3-C8 hydrocarbons, which arepartially or completely saturated.

As used herein, aryl groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl).

Heteroaryl groups, as used herein, is an aromatic ring system having atleast one heteroatom such as nitrogen, sulfur or oxygen. Heteroarylgroups include thienyl (also referred to herein as “thiophenyl”),pyridyl, pyrrolyl, benzofuranyl, isoxazolyl, and pyrimidinyl.

An aryl-C1-C4-alkyl group, as used herein, is an aryl substituent thatis linked to a compound by an alkyl group having from one to four carbonatoms.

A heteroaryl-C1-C4-alkyl group, as used herein, is a heteroarylsubstituent that is linked to a compound by an alkyl group having fromone to four carbon atoms.

A cycloalkyl-C1-C4-alkyl group, as used herein, is a cycloalkylsubstituent that is linked to a compound by an alkyl group having fromone to four carbon atoms.

An aminoalkyl group is an alkyl group having from one to six carbonatoms which is substituted with at least one amine represented by—NR12R12 in which each R12 are, independently, a C1-C6 alkyl or both R12taken together with the nitrogen to which they are attached form a fiveor six membered heterocycloalkyl.

A heterocycloalkyl is a non-aromatic ring which contains one or moreoxygen, nitrogen or sulfer (e.g., morpholine, piperidine, piperazine,pyrrolidine, and thiomorpholine). Preferred heterocycloalkyl group ismorpholine.

Substituents for aryl, heteroaryl and cycloalkyl groups include halo,carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,nitro, cyano, CHO, hydroxyl, C1-C4 alkanoic acid and —C(O)NR13R13 inwhich each R13, independently, H or a C1-C4 alkyl.

Substituents for thiophen-2,5-diyl and phenylene include H, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy.

Preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula II:

In Structural Formula II, R1, R2 and R5 are as defined for StructuralFormula I while R6 are each, independently, H, C1-C4 alkyl or C1-C4alkoxy. In addition, R7 are each, independently, H, halo, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl,C3-C8 cycloalkyl, thienyl or phenyl. R8 are each, independently, H,halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl, phenyl or togetherwith the phenyl to which they are bound form naphthyl,1,2,3,4-tetrahydronaphthyl, quinolyl or benzo[1,3]dioxol-5-yl. Further,R9 is C1-C4 alkyl or C1-C4 haloalkyl.

Examples of compounds having Structural Formula II include, forinstance, the compounds described in Examples 1-89 and 92-140.

More preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula III:

In Structural Formula III, R5, R6, R7 and R8 are as defined forStructural Formulas I and II while R10 is an unsubstituted orsubstituted group selected from 2-thienyl, 3-thienyl, phenyl, cyclohexylor 1-methyl-cyclohexyl.

Even more preferably, the compounds of the present invention, and withtheir respective pharmaceutical compositions, have a structurerepresented by Structural Formula IV or V.

In Structural Formulas IV and V, R7 and R8 are as defined for StructuralFormula II while R11 is H, halo or C1-C4 alkyl.

In an alternate embodiment, the compounds of the present invention, andwith their respective pharmaceutical compositions, have a structurerepresented by Structural Formula VI.

In Structural Formula VI, R1, R2, R3, R4 and R5 are as defined forStructural Formula I while V is C, C(OH) or C(O).

The compounds of Structural Formula I contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

In a more preferred embodiment, the compounds of the present inventionare S-enantiomers. In a most preferred embodiment, the compounds are(S)-3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionic acid,(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid, and(S)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]phenyl}-2-methyl-2-p-tolyloxy-propionicacid.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. The present invention includes each diastereoisomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I and their salts may exist inmore than one crystal form. Polymorphs of compounds represented byStructural Formula I form part of this invention and may be prepared bycrystallization of a compound of Structural Formula I under differentconditions. For example, using different solvents or different solventmixtures for recrystallization; crystallization at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallization. Polymorphs may also be obtained byheating or melting a compound of Structural Formula I followed bygradual or fast cooling. The presence of polymorphs may be determined bysolid probe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

Certain compounds of Structural Formula I and their salts may exist inmore than one crystal form and the present invention includes eachcrystal form and mixtures thereof.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I which are substantially non-toxic to mammals.Typical pharmaceutically-acceptable salts include those salts preparedby reaction of the compounds of the present invention with a mineral ororganic acid or an organic or inorganic base. Such salts are known asbase addition salts, respectively. It should be recognized that theparticular counterion forming a part of any salt of this invention isnot of a critical nature, so long as the salt as a whole ispharmaceutically-acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

By virtue of its acidic moiety, a compound of Structural Formula I formssalts with pharmaceutically acceptable bases. Some examples of baseaddition salts include metal salts such as aluminum; alkali metal saltssuch as lithium, sodium or potassium; and alkaline earth metal saltssuch as calcium, magnesium, ammonium, or substituted ammonium salts.Examples of substituted ammonium salts include, for instance, those withlower alkylamines such as trimethylamine, triethylamine;hydroxyalkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydro-abietylamine, glucamine, N-methylglucamine; bases of thepyridine type such as pyridine, collidine, quinine or quinoline; andsalts of basic amino acids such as lysine and arginine.

Examples of inorganic bases include, without limitation, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like.

Compounds of Structural Formula I, which are substituted with a basicgroup, may exist as salts with pharmaceutically acceptable acids. Thepresent invention includes such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures],succinates, benzoates and salts with amino acids such as glutamic acid.

These salts may be prepared by methods known to those skilled in theart.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Prodrugs are compounds of the present invention, which have chemicallyor metabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention which arepharmaceutically active in vivo. Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularlypreferred esters as prodrugs are methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

Methyl ester prodrugs may be prepared by reaction of the acid form of acompound of Formula I in a medium such as methanol with an acid or baseesterification catalyst (e.g., NaOH, H₂SO₄). Ethyl ester prodrugs areprepared in similar fashion using ethanol in place of methanol.Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Structural Formula I (in a medium such asdimethylformamide) 4-(2-chloroethyl)morphine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

The term, “active ingredient” means the compounds generically describedby Structural Formula I as well as the salts, solvates, and prodrugs ofsuch compounds.

The term “pharmaceutically acceptable” means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of thecomposition, and not deleterious to the recipient thereof.Pharmaceutical compositions of the present invention are prepared byprocedures known in the art using well known and readily availableingredients.

“Preventing” refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein.

“Treating” refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorate the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of a compound, orof its salt, solvate, hydrate or prodrug thereof, that will elicit thebiological or medical response of a tissue, system, or mammal. Such anamount can be administered prophylactically to a patient thought to besusceptible to development of a disease or condition. Such amount whenadministered prophylactically to a patient can also be effective toprevent or lessen the severity of the mediated condition. Such an amountis intended to include an amount which is sufficient to modulate a PPARreceptor, such as a PPARα or PPARγ receptor, which mediate a disease orcondition. Conditions mediated by PPARα or PPARγ receptors includediabetes mellitus, cardiovascular disease, Syndrome X, obesity andgastrointestinal disease.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The human to whom thecompounds and compositions of the present invention are administered hasa disease or condition in which control blood glucose levels are notadequately controlled without medical intervention, but wherein there isendogenous insulin present in the human's blood. Non-insulin dependentdiabetes mellitus (NIDDM) is a chronic disease or conditioncharacterized by the presence of insulin in the blood, even at levelsabove normal, but resistance or lack of sensitivity to insulin action atthe tissues. The compounds and compositions of the present invention arealso useful to treat acute or transient disorders in insulinsensitivity, such as sometimes occur following surgery, trauma,myocardial infarction, and the like. The compounds and compositions ofthe present invention are also useful for lowering serum triglyceridelevels. Elevated triglyceride level, whether caused by geneticpredisposition or by a high fat diet, is a risk factor for thedevelopment of heart disease, stroke, and circulatory system disordersand diseases. The physician of ordinary skill will know how to identifyhumans who will benefit from administration of the compounds andcompositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof to a hyperglycemic human or non-human mammalin need thereof.

They are useful as therapeutic substances in preventing or treatingSyndrome X, diabetes mellitus and related endocrine and cardiovasculardisorders and diseases in human or non-human animals.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating aPPARα or PPARγ mediated condition, separately or in combination.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,raising the plasma level of high density lipoprotein, and for treating,preventing or reducing the risk of developing atherosclerosis, and forpreventing or reducing the risk of having a first or subsequentatherosclerotic disease event in mammals, particularly in humans. Ingeneral, a therapeutically effective amount of a compound of the presentinvention (1) typically reduces serum glucose levels, or morespecifically HbA1c, of a patient by about 0.7% or more; (2) typicallyreduces serum triglyceride levels of a patient by about 20% or more, and(3) increases serum HDL levels in a patient. Preferably, HDL levels willbe increased by about 30% or more.

Additionally, an effective amount of a compound of Structural Formula Iand a therapeutically effective amount of one or more active agentsselected from a group consisting of: antihyperlipidemic agent, plasmaHDL-raising agents, antihypercholesterolemic agents, fibrates, vitamins,aspirin, insulin secretogogues, insulin and the like can be usedtogether for the preparation of a medicament useful for theabove-described treatments.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of Structural Formula I actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity andthe complications associated with diabetes including cardiovasculardisease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition which contains a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or thereof and an insulin secretogogue such as biguamides,thiazolidinediones, sulfonylureas, insulin, or α-glucosidose inhibitorscan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, a compound of Structural Formula I and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguamides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salts, solvates and hydrates thereof, have valuablepharmacological properties and can be used in pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof the present invention, or pharmaceutically acceptable salts, estersor prodrugs thereof, in combination with one or more pharmaceuticallyacceptable excipients. Excipients are inert substances such as, withoutlimitation carriers, diluents, fillers, flavoring agents, sweeteners,lubricants, solubilizers, suspending agents, wetting agents, binders,disintegrating agents, encapsulating material and other conventionaladjuvants. Proper formulation is dependent upon the route ofadministration chosen. Pharmaceutical compositions typically containfrom about 1 to about 99 weight percent of the active ingredient whichis a compound of the present invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, powders, sachets,granules, dragees, capsules, liquids, elixers, tinctures, gels,emulsions, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores.

For oral administration in the form of a tablet or capsule, the activeingredient may be combined with an oral, non-toxic,pharmaceutically-acceptable carrier, such as, without limitation,lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate,calcium phosphate, calcium sulfate, sodium carbonate, mannitol,sorbitol, and the like; together with, optionally, disintegratingagents, such as, without limitation, cross-linked polyvinyl pyrrolidone,maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginicacid, or a salt thereof such as sodium alginate, and the like; and,optionally, binding agents, for example, without limitation, gelatin,acacia, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic gums, acacia, tragacanth, sodium alginate,carboxymethyl-cellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like. When adosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substance which may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

In powders, the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

All formulations for oral administration should be in dosages suitablefor such administration. Particularly suitable compositions for oraladministration are unit dosage forms such as tablets and capsules.

For parental administration the compounds of the present invention, orsalts thereof, can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. Formulations for injection maybe presented in unit dosage form, such as in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The pharmaceutical forms suitablefor injectable use include sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the form must be sterile andmust be fluid to the extent that each syringability exists. It must bestable under the conditions of manufacture and storage and must bepreserved against any contamination. The carrier can be solvent ordispersion medium containing, for example, water, preferably inphysiologically compatible buffers such as Hanks's solution, Ringer'ssolution, or physiological saline buffer, ethanol, polyol (e.g.glycerol, propylene glycol and liquid polyethylene glycol), propyleneglycol and liquid polyethylene glycol), suitable mixtures thereof, andvegetable oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in a conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of a dry powderinhaler, or an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00The Active Ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows:

Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone (as 10% solution in water) 4 mg Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mgThe Active Ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of Active Ingredient, are made asfollows:

Active Ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mgMagnesium stearate  2 mg Total 200 mg The Active Ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of Active Ingredient, are made asfollows:

Active Ingredient   225 mg Saturated fatty acid glycerides 2,000 mgTotal 2,225 mgThe Active Ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of Active Ingredient per 5 ml dose,are made as follows:

Active Ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified waterto total 5 mlThe Active Ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

Active Ingredient 100 mg Isotonic saline 1,000 mlThe solution of the above materials generally is administeredintravenously to a subject at a rate of 1 ml per minute.In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new PPARα and PPARγ agonists.

SYNTHESIS

Compounds of the present invention have been formed by reacting a2-(R1-substituted)-5-R2-substituted-oxazol-4-yl ethyl sulfonyl esterwith a 3-(4-hydroxyphenyl)-2-R4-oxy-propionic acid or a3-(5-hydroxy-thiophen-2,5-diyl)-2-R4-oxy-propionic acid. Generally, thesulfonyl ester chemical intermediates have been synthesized through twodifferent routes, shown in Schemes IA and IB, while Scheme II is typicalof the synthethic method used to make the propionic acid chemicalintermediate. The formation of the compounds of the present inventionfrom these chemical intermediates is shown in Scheme III.

In Scheme IA, the first step is a condensation of a dionemonooximerepresented by Structural Formula IA-1 with a R1-substituted aldehyderepresented by Structural Formula IA-2 in the presence of an acid suchas aqueous concentrated hydrochloric acid or, preferably, acetic acidwhich is saturated with hydrogen chloride gas. Typically, hydrogenchloride is bubbled through a solution of the dionemonooxime and theR1-substituted aldehyde in acetic acid, which is held at a constanttemperature of about 0° C. to about 20° C. for about 15 minutes to about1 hour. The product of the condensation is an oxazole n-oxiderepresented by Structural Formula IA-3.

The oxazole n-oxide is then treated with phosphorous oxyhalide, such asphosphorous oxychloride or phosphorous oxybromide in an inert solventsuch as dichloromethane or chloroform to form a2-(R1-substituted)-4-halomethyl-oxazole represented by StructuralFormula IA-4. The reaction typically is carried out at the refluxtemperature of the solvent used and is complete in about 15 minutes toabout 1 hour.

The 2-(R1-substituted)-4-chloromethyl-oxazole is then treated with acyanide and an iodide salt to form a2-(R1-substituted)-4-cyanomethyl-oxazole represented by StructuralFormula IA-5. The reaction is typically carried out in a polar, aproticsolvent such as dimethylformamide at a temperature of about 30° C. toabout 120° C. for about 1 hour to about 6 hours. Preferably, the cyanideand iodide salts are potassium cyanide and potassium iodide.

The cyano group of the a 2-(R1-substituted)-4-cyanomethyl-oxazole isconverted to a carboxylic acid group by treatment with a alkali metalhydroxide to form a 2-(R1-substituted)-4-carboxymethyl-oxazolerepresented by Structural Formula IA-6. The reaction is generallycarried out in an aqueous solution at about 80° C. to about 100° C. Theconcentration of the alkali metal hydroxide in the aqueous solution istypically about 25% to about 85% (weight/volume). Preferably, the alkalimetal hydroxide is potassium hydroxide.

The 2-(R1-substituted)-4-carboxymethyl-oxazole is then treated with acarboxylic acid reducing agent, such as borane or lithium aluminumhydride, to form the 2-(R1-substituted)-4-(2-hydroxyethyl)-oxazoleintermediate represented by Structural Formula IA-7. The reaction istypically carried out under anhydrous conditions in an ether solventsuch as tetrahydrofuran (THF), dioxane, or ethyl ether. When borane isthe reducing agent used, it typically forms a complex with the ethersolvent such as a BH₃-THF complex. A solution having a concentration ofabout 0.5 M to about 1.5 M borane complex in the ether solvent is addeddropwise to a solution of 0.1 M to 1.3 M of the2-(R1-substituted)-4-carboxymethyl-oxazole in the ether solvent. Thereaction temperature is about 20° C. to about 40° C. Typically, thereaction is complete in about 1 hour to about 5 hours.

The chemical intermediate, represented by Structural Formula IA-7, isthen converted into a 2-(R1-substituted-oxazol-4-yl)ethyl sulfonyl esterrepresented by Structural Formula IA-8 by treatment with a sulfonylanhydride, such as tosyl anhydride or mesyl anhydride, or a sulfonylhalide, such as tosyl chloride or mesyl chloride, in the presence of abase. The reaction is typically carried out in an aprotic solvent suchas methylene chloride in the presence of an aprotic base such aspyridine or N,N-dimethylaminopyridine (DMAP). The reaction is completein about 0.5 hours to about 5 hours.

In Scheme IB, the first step is a condensation of .-methyl L-aspartaterepresented by Structural Formula IB-1 with a R1-substituted acidchloride in the presence of mild base to form the amide represented byStructural Formula IB-3. Typically, the reaction is carried out in anacetone/water media in the presence of a carbonate base, such aspotassium or sodium carbonate. The R1-substituted acid chloride is addedto a solution of .-methyl L-aspartate in acetone/water at about 0° C. toabout 10° C. and the reaction warms to ambient temperature for about 60minutes to 2 hours.

The acid is then treated with a base such as pyridine and an anhydridesuch as acetic, n-propyl or trifluoroacetic anhydride to form theR2-substituted ketone represented by Structural Formula IB-4. Thereaction is typically carried out at 90° C. and is complete in about 90minutes to about 2 hours.

Cyclo-dehydration of the R2-substituted ketone is completed with aprotic acid such as sulfuric acid in the presence of acetic anhydride toform the 2-(R1-substituted)-5-(R2-substituted)-oxazole represented byStructural Formula IB-5. Alternatively, the ketone can be treated with aphosphorus oxyhalide, such as phosphorous oxychloride or phosphorousoxybromide in a polar, aprotic solvent such as dimethylformamide. Inboth methods, the reaction is heated to about 90° C. and is complete inabout 15 minutes to 30 minutes.

The 2-(R1-substituted)-5-(R2-substituted)-oxazole is treated withaqueous base, such as aqueous sodium hydroxide in an alcohol solvent atabout 25° C. to about 45° C. for about 30 minutes to form thecorresponding acid. The acid is treated with a carboxylic acid reducingagent, such as borane or lithium aluminum hydride, to form the2-(R1-substituted)-4-(2-hydroxyethyl)-oxazole intermediate representedby Structural Formula IA-7. The reaction is typically carried out asdescribed for the formation of the intermediate represented byStructural Formula IA-7 in Scheme IA.

The compound represented by Structural Formula II-7 can be prepared bythe method depicted in Scheme II. In this method, an α-bromoesterrepresented by compound II-1 is reacted with a phenol represented bycompound II-2 to form an α-phenoxy ester represented by compound II-3.This reaction is typically carried out in an anhydrous polar solventsuch as DMF at a temperature of about 60° C. to about 110° C. Thereaction time is about 10 h to about 20 h.

The α-phenoxy ester is then deprotonated with an alkylamide lithiumcompound, such as LDA (1.1 eq), to form the enol. This reaction istypically performed in an anhydrous, polar, aprotic solvent at atemperature of about −20° C. to about −110° C. After about 5 min toabout 20 min. a 4-benzyloxybenzaldehyde represented by compound II-4 isadded and the reaction is stirred for about 5 min. to about 30 min.,then quenched with an aqueous solution of ammonium chloride to form a3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-phenoxy-propanoic esterrepresented by Structure II-5.

A solution of3-(4-benzyloxyphenyl)-3-hydroxy-2-substituted-2-phenoxy-propanoic esterin an anhydrous aprotic solvent at a temperature of about −10° C. toabout 10° C. was treated with an ether complex of boron trifluoride andtriethylsilane. The reaction is gradually allowed to warm to roomtemperature then stirred for about 1 h to about 2.5 h. The mixture isquenched by adding an aqueous base to form3-(4-benzyloxyphenyl)-2-substituted-2-phenoxy-propanoic esterrepresented by Structural Formula II-6.

The compound represented by Structural Formula II-6 is then treated toremove the benzyl protecting group to form the phenol represented byStructural Formula II-7. Methods of removing a benzyl protecting groupfrom a phenol can be found in Green, et al., Protective Groups inOrganic Synthesis, 2^(nd) edition, (1991), John Wiley & Sons, Inc., NewYork, pages 156-158, the entire teachings of which are incorporatedherein by reference. A preferred method of removing a benzyl protectinggroup is by treating the compound represented by Structural Formula II-3with hydrogen in the presence of palladium on carbon (Pd—C) catalyst.

In Scheme III, the 2-(oxazol-4-yl)ethyl sulfonyl ester is then reactedwith a phenol represented by Structural Formula II-7 in the presence ofa metal carbonate, such as cesium carbonate, to form a2-(3-{2-[2-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoic acid esterrepresented by Structural Formula III-1. In Structural Formula II-7, R3,R4 and R6 are as previously defined while R20 is a C1-C4 alkyl. Thereaction is typically carried out in a polar, aprotic solvent such asdimethylformamide at about 40° C. to about 70° C. and is allowed toproceed for about 10 hours to about 24 hours. The reactants (i.e., thecompounds represented by Structural Formulas IA-8 and II-7) are presentin about equal molar amounts or with about 0.1 M to about 0.5 M excessof the sulfonyl ester compound represented by Structural Formula IA-8.The cesium carbonate is present in about one molar equivalent to about1.5 molar equivalents with respect to the sulfonyl ester.

Alternatively, the 2-(oxazol-4-yl)ethyl sulfonyl ester is reacted with aphenol represented by Structural Formula II-7 in the presence of ahindered base to form a3-(4-{2-[2-oxazol-4-yl]ethoxy}-phenyl)-2-methyl-2-phenoxy-propanoic acidester represented by Structural Formula III-1. The reaction is typicallycarried out in a polar solvent such as an alcohol at about 40° C. toabout 70° C. and is allowed to proceed for about 24 hours to about 48hours. The reactants (i.e., the compounds represented by StructuralFormulas IA-8 and II-7) are present in about equal molar amounts. Thealkaline metal carbonate is present in about 20 molar equivalents and ispreferably bound to an inert solid support such as polystyrene.

Hydrolysis of the 2-(3-{2-[2-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoicacid ester, represented by Structural Formula III-1 wherein R20 is aC1-C4 alkyl, is typically carried out in an alcohol solvent in thepresence of an excess of aqueous alkali metal hydroxide. The reaction isheated at about 50° C. to about 60° C. and is allowed to proceed forabout 10 hours to about 24 hours to form a2-(3-{2-[2-oxazol-4-yl]ethoxy}-2-phenoxy)-alkanoic acid represented byStructural Formula III-1 wherein R20 is H.

EXEMPLIFICATION Instrumental Analysis

Infrared spectra were recorded on a Perkin Elmer 781 spectrometer. ¹HNMR spectra were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the δ scale, multiplicity(b=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the δ scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). Combustionanalyses were performed by Eli Lilly & Company MicroanalyticalLaboratory. High resolution mass spectra were obtained on VG ZAB 3F orVG 70 SE spectrometers. Analytical thin layer chromatography wasperformed on EM Reagent 0.25 mm silica gel 60-F plates. Visualizationwas accomplished with UV light.

Standard Synthesis Procedures

Certain standard synthesis procedures were used in preparing many of theexemplified compounds of the present invention. These standardprocedures were:

Standard Procedure (A): Toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester (0.47 g, 0.132 mmol) wasadded to a one dram, screw-cap vial and diluted with ethanol (0.5 mL).To this solution are added3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (0.5 mLof a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (100-125 mg, 2.6 mmol/g) and thevial was tightly closed. The reaction vessel was heated in a blockheater for 24-48 h at 55° C., or until TLC or MS analysis indicates thedisappearance of starting materials. The suspension was filtered whilewarm and the residue washed with ethanol (1 mL). The solution wastreated with aqueous NaOH (5N solution, 100 μl) and the vial resealedtightly. The solution was heated in a block heater at 55° C. for 3-16 h,or until MS analysis indicates the completion of the hydrolysis. Thesolvents are removed with a stream of nitrogen or under reduced pressureand the residue redissolved in 1 mL water. The solution was acidifiedwith aqueous HCl (5N solution, 150 μl), often causing precipitation ofproduct. The suspension was diluted with dichloromethane (3 mL) and theresultant biphasic solution was filtered through a Chrom-Elut column toremove water. The filtrate was concentrated in vacuo and the resultantresidue was purified by mass-directed HPLC to provide analytically purematerial. Overall yield after purification 25%.Standard Procedure (B): A mixture of3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester(0.095 g, 0.030 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (0.108 g, 0.030 mmol) and325 mesh K₂CO₃ (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated toreflux for 24 h under N₂. Aqueous 5N NaOH (0.5 mL) and additionalethanol (1 mL) was added to the reaction mixture and it was heated atreflux for an additional 2 h. The reaction was cooled and the solventremoved in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL),extracted with water and CH₂Cl₂ and the organic layer dried by passingit through a Varian Chem Elut 1003 cartridge. The solvent was removed invacuo to give 0.134 g of crude product which was purified by LCMS togive 0.036 g (25%) of analytically pure2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-m-tolyloxy-propionicacid.

EXEMPLIFIED COMPOUNDS Example 1rac-3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound, shown above, was made as described below.

Step A 2-Phenoxypropionic acid ethyl ester

Phenol (28.5 g, 0.30 mol), Cs₂CO₃ (197.0 g, 0.61 mol), and ethyl2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrousN,N-dimethylformamide (DMF) (1000 mL) and stirred at 90° C. under anatmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. Theresidue was dissolved in ethyl acetate (300 mL) and washed twice withwater and once with brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to produce 2-phenoxypropionic acid ethyl ester,shown above, as a golden oil (48.5 g, 83%) ¹H NMR (250 MHz, CDCl₃): δ7.31 (d, 2H, J=7.8), 7.02 (t, 1H, J=7.9), 6.93 (d, 2H, J=7.8), 4.79 (q,1H, J=6.1), 4.26 (q, 2H, J=7.2), 1.66 (d, 3H, J=6.1), 1.24 (t, 3H,J=7.2). MS [EI⁺] 195 (M+H)⁺.

Step B 2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethylester

A solution of lithium diisopropylamide (LDA) (16.5 mL, 24.7 mmol, 1.5Min cyclohexane) was cooled to −78° C. in a dry ice/acetone bath and thenadded to a solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (4.79 g, 24.7 mmol) in anhydrous tetrahydrofuran (THF)(30 mL) also cooled to −78° C. under an atmosphere of nitrogen. After 5min, 4-benzyloxybenzaldehyde (4.76 g, 22.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to provide acolorless oil (3.84 g, 42%) as a mixture of inseparable diastereomers of2-phenoxy-3-(4-benzyloxy-phenyl)-3-hydroxy-2-methylpropionic acid ethylester which was used without further characterization or purification.R_(f)=0.32 in 4:1 hexanes:ethyl acetate.

2-Phenoxy-3-(4-benzyloxyphenyl)-3-hydroxy-2-methylpropionic acid ethylester (3.84 g, 9.5 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to 0° C.and treated with BF₃-Et₂O (1.16 mL, 9.5 mmol) and triethylsilane (1.51mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed toambient temperature. Saturated aqueous Na₂CO₃ (15 mL) was added and themixture was stirred vigorously. The solution was partitioned and theorganic layer was washed twice with water and brine, dried over Na₂SO₄,and concentrated in vacuo to produce2-phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester,shown above, as a colorless oil (1.34 g, 36%). R_(f)=0.90 (9:1hexanes:ethyl acetate). ¹H NMR (300 MHz, CDCl₃): δ 7.36-7.42 (m, 3H),7.34 (t, 1H), 7.17-7.24 (m, 5H), 6.98 (t, 1H), 6.91 (d, 2H), 6.83 (d,2H), 5.05 (s, 2H), 4.22 (q, 1H, J=7.1), 3.26 (d, 1H, J=13.7), 3.13 (d,1H, J=13.7), 1.40 (s, 3H), 1.22 (t, 3H, J=7.1). MS [EI⁺] 408 (M+NH₄)⁺.

Step C 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester

2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (830mg, 2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5%palladium on carbon (300 mg), and then stirred under an atmosphere ofhydrogen for 20 h. The suspension was filtered through celite andconcentrated in vacuo to produce3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl estercolorless oil (563 mg, 89%) ¹H NMR (300 MHz, CDCl₃): δ 7.23 (t, 2H),7.13 (d, 2H), 6.96 (t, 1H), 6.83 (d, 2H), 6.76 (d, 2H), 4.19 (q, 1H,J=7.1), 3.23 (d, 1H, J=12.4), 3.08 (d, 1H, J=12.4), 1.39 (s, 3H), 1.22(t, J=7.1). MS [EI+] 318 (M+H)⁺, [EI−] 359 (M+OAc⁻).

Additional 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethylester (approx 48 g), prepared in the same manner, was purified by chiralchromatography to provided the individual enantiomers (Chiralcel OD,8×27 cm, 7% IPA/heptane, 248 nm; (S)-isomer: 97.2% ee; (R)-isomer: >99%ee).

Step D3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495mg, 1.7 mmol), toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester (766 mg, 2.2 mmol) andCs₂CO₃ (700 mg, 2.2 mmol) were combined in anhydrous DMF (25 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled and diluted with ethyl acetate (100 mL), and washed withwater then brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo to a viscous yellow oil. The residue was purifiedby flash column chromatography (100 g silica, 60×15 mL fractions,gradient elution 0-20% ethyl acetate in hexanes) to provide the ethylester as a colorless oil (48%). ¹H NMR (300 MHz, CDCl₃): δ 7.96 (m, 2H),7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H), 6.93 (t, 1H), 6.82 (m, 4H),4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H), 3.06 (d, 1H), 2.95 (t, 2H),2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486 (M+H)⁺, [EI−] 484 (M−H)⁺.

Step E 3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2methyl-2-phenoxy-propionic acid

The title compound, was prepared as follows.3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester (4.6 g, 9.5 mmol) was dissolved in methanol (75 ml) andtreated with 2.0 N NaOH (75 ml) with vigorous stirring, causing slightprecipitation. The suspension was heated for 18 h at 55 C, allowing fulldissolution of all reagents. The methanol was then removed in vacuo andthe aqueous residue was acidified with 5.0 N HCl (75 ml) at 0° C. Thesuspension was extracted into ethyl acetate and the orgnaic solutiondried over Na₂SO₄ and concentrated to produce a white solid (94%).

¹H NMR (300 MHz, d₆-DMSO): δ 7.87 (m, 2H), 7.44 (m, 3H), 7.21 (dd, 2H,J=7.8, 8.8), 7.10 (d, 2H, J=8.8), 6.91 (t, 1H, J=8.8), 6.81 (d, 2H,J=7.8), 6.77 (d, 2H, J=7.8), 4.14 (t, 2H, J=6.6), 3.14 (d, 1H, J=12.0),3.01 (d, 1H, J=12.0), 2.88 (d, 2H, J=6.6), 2.31 (s, 3H), 1.24 (s, 3H).MS [EI+] 458 (M+H)⁺, 480 (M+Na)⁺, [EI−] 456 (M−H)⁺.

Example 2(R)-3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

(R)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester,shown below,

from Example 1, Step C, and toluene-4-sulfonic acid2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester were reacted, as describedin Example 1, Step D, to provide(R)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester, shown below, as a colorless oil (61%). ¹H NMR (300MHz, CDCl₃): δ 7.96 (m, 2H), 7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H),6.93 (t, 1H), 6.82 (m, 4H), 4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H),3.06 (d, 1H), 2.95 (t, 2H), 2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486(M+H)⁺, [EI−] 484 (M−H)⁺.

The title compound was then prepared from this phenoxy propionic acidethyl ester, via the hydrolysis procedure of Example 1, Step E, toproduce a white solid (99%). ¹H NMR (300 MHz, d₆-DMSO): δ 7.87 (m, 2H),7.44 (m, 3H), 7.21 (dd, 2H, J=7.8, 8.8), 7.10 (d, 2H, J=8.8), 6.91 (t,1H, J=8.8), 6.81 (d, 2H, J=7.8), 6.77 (d, 2H, J=7.8), 4.14 (t, 2H,J=6.6), 3.14 (d, 1H, J=12.0), 3.01 (d, 1H, J=12.0), 2.88 (d, 2H, J=6.6),2.31 (s, 3H), 1.24 (s, 3H). MS [EI+] 458 (M+H)⁺, [EI−] 456 (M−H)⁺.

Example 3(S)-3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester,shown below,

from Example 1, Step C, and toluene-4-sulfonic acid2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester were reacted, as describedin Example 1, Step D, to provide(S)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester, shown below, as a colorless oil (41%). ¹H NMR (300MHz, CDCl₃): δ 7.96 (m, 2H), 7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H),6.93 (t, 1H), 6.82 (m, 4H), 4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H),3.06 (d, 1H), 2.95 (t, 2H), 2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486(M+H)⁺, [EI−] 484 (M−H)⁺.

The title compound was then prepared from this phenoxy propionic acidethyl ester, via the hydrolysis procedure of Example 1, Step E, toproduce a white solid (96%). ¹H NMR (300 MHz, d₆-DMSO): δ 7.87 (m, 2H),7.44 (m, 3H), 7.21 (dd, 2H, J=7.8, 8.8), 7.10 (d, 2H, J=8.8), 6.91 (t,1H, J=8.8), 6.81 (d, 2H, J=7.8), 6.77 (d, 2H, J=7.8), 4.14 (t, 2H,J=6.6), 3.14 (d, 1H, J=12.0), 3.01 (d, 1H, J=12.0), 2.88 (d, 2H, J=6.6),2.31 (s, 3H), 1.24 (s, 3H). MS [EI+] 458 (M+H)⁺, [EI−] 456 (M−H)⁺.

Example 4rac-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester andtoluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethylester, shown below,

were reacted, as described in Example 1, Step D, to provide2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester, shown below, as a colorless oil (30%). ¹H NMR (300MHz, CDCl₃): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H),7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H),4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H),1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)⁺, [EI−] 490 (M−H)⁺.

The title compound was then prepared from this phenoxy propionic acidethyl ester, using the hydrolysis procedure of Example 1, Step E, toprovide a white solid (88%). ¹H NMR (300 MHz, d₆-DMSO): δ 7.70 (d, 1H,J=5.1), 7.57 (d, 1H, J=3.5), 7.23 (t, 2H, J=7.4), 7.15 (dd, 1H, J=3.5,5.1), 7.12 (d, 2H, J=8.6), 6.93 (dd, 1H, J=7.4, 7.8), 6.83 (d, 2H,J=8.6), 6.79 (d, 2H, J=7.8), 4.14 (t, 2H, J=6.6), 3.15 (d, 1H, J=13.7),3.03 (d, 1H, J=13.7), 2.87 (t, 2H, J=6.6), 2.30 (s, 3H), 1.26 (s, 3H).MS [EI+] 464 (M+H)⁺, [EI−] 462 (M−H)⁺ HPLC: T=2.78 min, purity 99%.

Example 5(R)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

(R)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl esterand toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester were reacted, asdescribed in Example 1, Step D, to provide(R)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]phenyl}-2-phenoxypropionicacid ethyl ester, shown below, as a colorless oil (54%). ¹H NMR (300MHz, CDCl₃): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H),7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H),4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H),1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)⁺, [EI−] 490 (M−H)⁺.

The title compound was then prepared using the hydrolysis procedure ofExample 1, Step E, to provide a white solid (78%). ¹H NMR (300 MHz,d₆-DMSO): • 7.70 (d, 1H, J=5.1), 7.57 (d, 1H, J=3.5), 7.23 (t, 2H,J=7.4), 7.15 (dd, 1H, J=3.5, 5.1), 7.12 (d, 2H, J=8.6), 6.93 (dd, 1H,J=7.4, 7.8), 6.83 (d, 2H, J=8.6), 6.79 (d, 2H, J=7.8), 4.14 (t, 2H,J=6.6), 3.15 (d, 1H, J=13.7), 3.03 (d, 1H, J=13.7), 2.87 (t, 2H, J=6.6),2.30 (s, 3H), 1.26 (s, 3H). MS [EI+] 464 (M+H)⁺, [EI−] 462 (M−H)⁺.

Example 6(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxypropionicacid

(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester andtoluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethylester were reacted, as described in Example 1, Step D, to provide(S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]phenyl}-2-phenoxypropionicacid ethyl ester, shown below, as a colorless oil (48%). ¹H NMR (300MHz, CDCl₃): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H),7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H),4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H),1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)⁺, [EI−] 490 (M−H)⁺.

The title compound was then prepared using the hydrolysis procedure ofExample 1, Step E, to provide a white solid (78%). ¹H NMR (300 MHz,d₆-DMSO): δ 7.70 (d, 1H, J=5.1), 7.57 (d, 1H, J=3.5), 7.23 (t, 2H,J=7.4), 7.15 (dd, 1H, J=3.5, 5.1), 7.12 (d, 2H, J=8.6), 6.93 (dd, 1H,J=7.4, 7.8), 6.83 (d, 2H, J=8.6), 6.79 (d, 2H, J=7.8), 4.14 (t, 2H,J=6.6), 3.15 (d, 1H, J=13.7), 3.03 (d, 1H, J=13.7), 2.87 (t, 2H, J=6.6),2.30 (s, 3H), 1.26 (s, 3H). MS [EI+] 464 (M+H)⁺, [EI−] 462 (M−H)⁺.

Example 72-Methyl-3-(4-{2-[5-methyl-2-cyclohexyl-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid

The title compound, shown above, was synthesized as follows:

Step A 2-(Cyclohexanecarbonyl-amino)-succinic acid 4-benzyl ester

Benzyl L-aspartate (25.0 g, 0.109 moles), DI water (325 mL), acetone (25mL), and Na₂CO₃ (41.1 g, 0.384 mol) were combined and cooled to 8° C.Cyclohexanecarbonyl chloride (16 mL, 0.120 mol) was added dropwise viaaddition funnel over 10 min. The reaction was allowed to warm to ambienttemperature and stirred for at least 90 min. Concentrated HCl (50 mL)was added to the slurry until the pH was <4.0 (pH paper). The mixturewas stirred for an additional 45 min, and then filtered. The solid wasrinsed with DI water (2×25 mL) and dried under vacuum at 30° C.overnight to provide 34.3 g of crude amide. Further purification was notnecessary.

Step B 3-(Cyclohexanecarbonyl-amino)-4-oxo-pentanoic acid benzyl ester

In a 2 L flask, 2-(cyclohexanecarbonyl-amino)-succinic acid 4-benzylester (34.2 g, 0.102 moles), pyridine (155 mL) and acetic anhydride (127mL) were combined. The reaction mixture was heated to 90° C. for 2 h andthen cooled to ambient temperature. DI water (950 mL) was added slowlyand the reaction mixture cooled to ambient temperature before addingconc. HCl (50 mL) to the slurry until the pH was <4.0 (pH paper). Afterstirring for 45 min, the solid was filtered, rinsed with DI water (2×50mL) and then dried under vacuum at 40° C. overnight to obtain 26.0 g ofcrude ketone. Further purification was not necessary.

Step C (2-Cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid benzyl ester

Phosphorous oxychloride (22 mL, 0.235 moles, 3.0 eq) was added dropwiseto a solution of 3-(cyclohexanecarbonyl-amino)-4-oxo-pentanoic acidbenzyl ester (26.0 g, 0.078 moles) in DMF (330 mL). The mixture washeated to 90° C. for 30 min, and then cooled to ambient temperaturebefore diluting by slowly adding DI water (600 mL, Caution, exothermic).The mixture was cooled to ambient temperature and extracted with MTBE(3×150 mL). The combined organic phases were washed with DI water, brine(150 mL), dried over MgSO₄ and concentrated to obtain 21.1 g as a brownoil. Further purification was not necessary.

Step D (2-Cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid

(2-Cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid benzyl ester (23.8 g,0.076 moles), 2B-3 ethanol (120 mL), DI water (95 mL) and KOH (10.0 g,0.152 moles, 2 eq) were stirred at ambient temperature for 60 min oruntil HPLC showed disappearance of benzyl ester. The reaction mixturewas concentrated and then conc. HCL was added to the oily residue untilthe pH=1 (pH paper). The reaction mixture was partitioned with MTBE (100mL) and then the organic layer was washed with DI water, brine (1×120mL), dried over MgSO₄ and concentrated to obtain a brown semi-solid.

The brown semi-solid was dissolved in 5% Na₂CO₃ (100 mL) and washed withMTBE (3×100 mL). The combined organic phases were back-extracted with 5%Na₂CO₃ (1×50 mL). The combined aqueous layers were acidified to pH=1with conc. HCl and extracted with MTBE (3×50 mL). The combined organicphases were washed with brine (1×50 mL), dried over MgSO₄ andconcentrated to obtain 9.5 g of acid. The ¹H NMR showed<1% benzylalcohol.

Step E 2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethanol

BH₃-THF complex (96 mL, 0.096 moles, 2.3 eq) was added dropwise viaaddition funnel to a solution of(2-cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid (9.4 g, 0.041 moles) inTHF (45 mL) over 50 min. The reaction mixture was stirred for 3 h, andthen quenched with MeOH (30 mL). After heating at 60° C. for 2 h, thereaction mixture was cooled to ambient temperature, concentrated and theresidue dissolved in CH₂Cl₂ (50 mL). The organic phase was washed with1N NaOH and brine (1×50 mL), dried over MgSO₄ and concentrated to obtain7.80 g of a yellow oil. The ¹H NMR was consistent with desired product.¹H NMR (400 MHz, CDCl₃) δ 3.73 (t, J=6.8 Hz, 2H), 2.58 (tt, J=11.6, 3.6Hz, 1H), 2.54 (t, J=6.8 Hz, 2H), 2.13 (s, 3H), 1.93-1.89 (m, 2H), 1.74(dt, J=12.8, 3.6 Hz, 2H), 1.67-1.62 (m, 1H), 1.41 (qd, J=12.0, 3.2 Hz,1H), 1.33-1.17 (m, 4H); MS (EI+) 210.1 (M+H), 232.1 (M+H+Na).

Step F Toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester

A solution of 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethanol, (8.7 g,41.6 mmol) in CH₂Cl₂ (120 mL) at ambient temperature was treated withpyridine (12 mL, 150 mmol), 4-dimethylamino pyridine (DMAP) (1.6 g, 13.1mmol), and tosyl anhyride (25.3 g, 77.5 mmol). After 18 h, the reactionmixture was partitioned with vigorous stirring between CH₂Cl₂ and 1NHCl. The aqueous layer was extracted with CH₂Cl₂ and then combinedorganic phases were washed with brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by Biotage chromatography (40 L,25% EtOAc/hexanes) to provide the product (9.8 g, 65%): ¹H NMR (400 MHz,CDCl₃) δ 7.67 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.16 (t, J=6.8Hz, 2H), 2.70 (t, J=6.8 Hz, 2H), 2.56 (tt, J=11.6, 3.6 Hz, 1H), 2.39 (s,3H), 2.13 (s, 3H), 1.93-1.89 (m, 2H), 1.74 (dt, J=12.8, 3.6 Hz, 2H),1.67-1.62 (m, 1H), 1.41 (qd, J=12.0, 3.2 Hz, 1H), 1.33-1.17 (m, 4H); MS(EI+) 364.1 (M+H).

Step G2-Methyl-3-(4-{2-[5-methyl-2-cyclohexyl-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid ethyl ester

3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (300mg, 1.0 mmol), toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (386 mg, 1.06 mmol)and Cs₂CO₃ (423 mg, 1.3 mmol) were combined in anhydrous DMF (7 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled, diluted with ethyl acetate (50 mL), and washed withwater and brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo to a viscous yellow oil. The residue was purifiedby flash column chromatography (100 g silica, 60×15 mL fractions,gradient elution 0-20% ethyl acetate in hexanes) to provide the ethylether compound as a colorless oil (177 mg, 28%).

Step H2-Methyl-3-(4-{2-[5-methyl-2-cyclohexyl-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid

The title compound was produced as follows.

2-Methyl-3-(4-{2-[5-methyl-2-cyclohexyl-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionicacid ethyl ester (175 mg, 3.6 mmol) in MeOH (7 mL) was treated with 2NNaOH (7 mL) and warmed to 55° C. After 18 h, the mixture wasconcentrated under reduced pressure and then acidified with 5N HCl to apH of 1. The solution was extracted with EtOAc and then the organicphases dried (Na₂SO₄), filtered and concentrated to a white foam (157mg, 88%): ¹H NMR (300 MHz, d₆-DMSO): δ 7.23 (t, J=7.2 Hz, 2H), 7.15 (d,J=8.3 Hz, 2H), 6.91 (dd, J=7.3, 7.2 Hz, 1H), 6.82 (d, J=8.3 Hz, 2H),6.80 (d, J=7.3 Hz, 2H), 4.16 (t, J=6.3 Hz, 2H), 3.14 (d, J=14.0 Hz, 1H),3.02 (d, J=14.0 Hz, 1H), 2.77 (t, J=6.3 Hz, 2H), 2.66 (m, 1H), 2.18 (s,3H), 1.90 (m, 1H), 1.86 (m, 1H), 1.69 (m, 2H), 1.61 (m, 1H), 1.42 (m,2H), 1.27 (m, 1H), 1.24 (s, 3H), 1.21 (m, 2H). MS [EI+] 464 (M+H)⁺,[EI−] 462 (M−H)⁺. HPLC: T=2.98 min, purity 94%.

Example 83-(4-{2-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid

Step A Toluene-4-sulfonic acid2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester

To a solution of 2-(3-bromophenyl)-5-methyl-4-oxazole ethanol (3.27 g,11.6 mmol) in CH₂Cl₂ (46 mL) at rt under N₂ was added pyridine (3.28 mL)and DMAP (0.43 g, 3.48 mmol) followed by portionwise addition of tosylanhydride (4.54 g, 13.9 mmol). The reaction exothermed to 32° C. and wasstirred 2 h before 1N HCl (50 mL) was added. The mixture was stirredvigorously 15 min, and then the organic phase was dried (MgSO₄) and thenconcentrated under reduced pressure. The residue was purified by columnchromatography (40 mL SiO₂, 50% EtOAc/hexanes) to providetoluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethylester (4.58 g, 91%) as a white powder: ¹H NMR (400 MHz, CDCl₃) δ 8.01(t, J=1.6 Hz, 1H), 7.80 (dt, J=7.6 Hz, J=1.6 Hz, 1H), 7.66 (d, J=8.4 Hz,2H), 7.53 (dt, J=7.6 Hz, J=1.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.19 (d,J=8.4 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 2.31 (s,3H), 2.24 (s, 3H); MS (EI) 437.0 (M+H)⁺.

Step B3-(4-{2-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid ethyl ester

This compound was prepared according to the procedure in Example 1, partD, using 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethylester (551.5 mg, 1.84 mmol) and toluene-4-sulfonic acid2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (1.04 g, 2.39mmol): R_(f)=0.54 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃) δ 8.14(s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.6Hz, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.98-6.95 (m,1H), 6.82 (d, J=8.4 Hz, 2H), 6.83-6.81 (m, 2H), 4.23 (t, J=6.8 Hz, 2H),4.20 (q, J=7.6 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.09 (d, J=14.0 Hz,1H), 2.97 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.6Hz, 3H); MS (EI)=564.2 (M+H)⁺.

Step C3-(4-{2-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid

The title compound was prepared according to the procedure in Example 1,Step E, using3-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)-2-methyl-2-phenoxypropionicacid ethyl ester (52 mg, 0.092 mmol): ¹H NMR (400 MHz, DMSO-d₆) δ 7.96(s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.91 (t, J=7.6 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.89 (t, J=7.6Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.75 (d, J=7.6 Hz, 2H), 4.12 (t, J=6.8Hz, 2H), 3.11 (d, J=13.6 Hz, 1H), 2.99 (d, J=13.6 Hz, 1H), 2.86 (t,J=6.8 Hz, 2H), 2.30 (s, 3H), 1.21 (s, 3H); MS (EI) 536.1 (M+H)⁺, 535.1(M−H)⁻.

Example 92-Methyl-3-(4-{2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid

In this synthesis, the following chemical intermediates and titlecompound were sequentially formed by the procedure of Example 7 using2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]ethanol, shown below.

Toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]ethyl ester, shown below:

¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.30 (t, J=8.4 Hz,2H), 4.12 (t, J=6.6 Hz, 2H), 2.76 (t, J=6.6 Hz, 2H), 2.42 (s, 3H), 2.17(s, 3H), 2.61-2.02 (m, 2H), 1.56-1.30 (m, 8H), 1.19 (s, 3H); MS (EI)378.2 (M+H)⁺.

2-Methyl-3-(4-{2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionicacid ethyl ester, shown below:

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.19 (m, 2H), 7.15-7.13 (m, 2H),6.99-6.95 (m, 1H), 6.83-6.80 (m, 4H), 4.20 (q, J=7.6 Hz, 2H), 4.14 (t,J=6.4 Hz, 2H), 3.29 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 2.89(t, J=6.4 Hz, 2H), 2.24 (s, 3H), 2.11 (broad m, 2H), 1.56-1.24 (v. broadm, 14H), 1.21 (t, J=7.6 Hz, 3H); MS (EI) 506.3 (M+H)⁺, 528.3 (M+Na)⁺.

The title compound,2-methyl-3-(4-{2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxy-propionicacid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t, J=7.2 Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 6.94 (t, J=7.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 6.80 (d, J=7.2Hz, 2H), 4.09 (t, J=6.8 Hz, 2H), 3.16 (d, J=13.2 Hz, 1H), 3.03 (d,J=13.2 Hz, 1H), 2.78 (t, J=6.8 Hz, 2H), 2.19 (s, 3H), 2.03-1.99 (m, 2H),1.48-1.27 (m, 11H), 1.16 (s, 3H); MS (EI) 478.3 (M+H)⁺, 476.3 (M−H)⁻.

Example 103-{4-[2-(2-Cyclohex-1-enyl-5-methyloxazol-4-yl)ethoxy]phenyl}-2-methyl-2-phenoxypropionicacid

In this synthesis, the following chemical intermediates and the titlecompound were sequentially prepared by the procedure of Example 7 using2-(2-cyclohex-1-enyl-5-methyloxazol-4-yl)ethanol, shown below.

Toluene-4-sulfonic acid 2-(2-cyclohex-1-enyl-5-methyloxazol-4-yl)ethylester, shown below: ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=8.0 Hz, 2H),7.27 (d, J=8.0 Hz, 2H), 6.61 (s, 1H), 4.23 (t, J=6.4 Hz, 2H), 2.76 (t,J=6.4 Hz, 2H), 2.42-2.20 (m, 8H), 1.72-1.63 (m, 6H); MS (EI) 362.2(M+H)⁺.

3-{4-[2-(2-Cyclohex-1-enyl-5-methyloxazol-4-yl)-ethoxy]phenyl}-2-methyl-2-phenoxypropionicacid ethyl ester, shown below:

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.19 (m, 2H), 7.15-7.13 (m, 2H), 6.97 (m,1H), 6.83-6.79 (m, 4H), 6.34 (s, 1H), 4.20 (q, J=7.6 Hz, 2H), 4.16 (t,J=6.8 Hz, 2H), 3.26 (d, J=13.6 Hz, 1H), 3.09 (d, J=7.6 Hz, 1H), 2.90 (t,J=6.8 Hz, 2H), 2.45-2.43 (m, 2H), 2.28 (s, 3H), 2.22-2.21 (m, 2H), 2.04(s, 3H), 1.73-1.64 (m, 4H), 1.38 (s, 3H), 1.26 (t, J=7.6 Hz, 3H); MS(EI) 490.3 (M+H)⁺, 512.3 (M+Na)⁺.

The title compound,3-{4-[2-(2-Cyclohex-1-enyl-5-methyloxazol-4-yl)-ethoxy]phenyl}-2-methyl-2-phenoxypropionicacid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (t, J=7.2 Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 6.94 (t, J=7.2 Hz, 1H), 6.82 (d, J=7.2 Hz, 2H), 6.80 (d, J=8.4Hz, 2H), 6.55 (s, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.16 (d, J=13.2 Hz, 1H),3.04 (d, J=13.2 Hz, 1H), 2.80 (t, J=6.8 Hz, 2H), 2.32 (bs, 2H), 2.23 (s,3H), 2.16-2.15 (m, 2H), 1.63-1.55 (m, 4H), 1.27 (s, 3H); MS (EI) 462.2(M+H)⁺, 460.3 (M−H)⁻.

Example 113-{3-Methoxy-4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy]phenyl}-2-methyl-2-phenoxypropionicacid

Step A3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionicacid

A stirred solution of LDA in cyclohexane (1.5 M) was cooled to −20° C.,to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in THF(80.3 mL) was slowly added, keeping the temperature below −10° C. Theresulting dianion solution was stirred for 15 min, then a solution of4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL)was added over 1 h, maintaining temperature below −10° C. Fifteenminutes after completion of aldehyde addition, the reaction mixture waspoured onto ice water (200 mL), and extracted using 1:2 Et₂O:hexane (500mL). The aqueous layer was isolated, extracted again with 1:2Et₂O:hexane (240 mL), then acidified with concentrated HCl until pH=3.The product acid was extracted into EtOAc (2×165 mL), which was driedover Na₂SO₄ and concentrated to an orange paste (16.5 g crude, 67%): MS(EI) 426.2 (M+NH₄)⁺, 407.2 (M−H)⁻.

Step B 3-(4-Benzyloxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid

A stirred solution of Et₃SiH (8.67 mL, 54.3 mmol) in CH₂Cl₂ (45 mL) wastreated with BF₃-Et₂O (6.8 mL, 54.3 mmol).3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionicacid (7.39 g, 18.1 mmol) in CH₂Cl₂ (90.5 mL) was then added dropwise viaaddition funnel, maintaining temperature below −7° C. After the additionwas complete, the reaction was stirred for 1.5 h at −10° C., thenquenched with 1 M NaOH (18.1 mL) and diluted with H₂O (12 mL). 1N HClwas used to adjust pH to 4, followed by separation of layers. Theaqueous layer was extracted with CH₂Cl₂ (2×15 mL), and combined organiclayers were washed first with 1N HCl (15 mL), then H₂O (15 mL), followedby drying over Na₂SO₄ and concentration to a gummy orange solid (6.86 g,97%): MS (EI) 410.2 (M+NH₄)⁺, 391.3 (M−H)⁻.

Step C 3-(4-Hydroxy-3-methoxy-phenyl)-2-methyl-2-phenoxypropionic acid

A solution of3-(4-benzyloxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid (6.86g, 17.5 mmol) in EtOH (175 mL) was added to 5% Pd/C (186 mg, 10 wt %).The mixture was purged first with nitrogen, then with H₂, which was thenapplied at 45 p.s.i. for 2 h. Pd/C was subsequently filtered off throughcelite, and the filtrate was concentrated to a crude oil (5.42 g, inexcess of theory). MS (EI) 301.2 (M−H)⁻.

Step D 3-(4-Hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acidethyl ester

A solution of 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxy-propionicacid (4.56 g, 15.08 mmol) in EtOH (150 mL) was treated with SOCl₂ andheated at 75° C. for 14 h, then cooled to rt and partitioned betweenEtOAc (300 mL) and H₂O (400 mL). The aqueous layer was removed andback-extracted with EtOAc (100 mL). Combined organic phases were washedwith 10% Na₂CO₃, which was isolated and back-extracted with EtOAc (100mL). Combined organic phases were washed with brine (200 mL), dried overNa₂SO₄, concentrated, and purified by column chromatography (200 g SiO₂,1:4 EtOAc:hexanes) to provide a colorless oil, which developed a greencolor over a 24-hour period. The material was taken up in EtOAc andfiltered through celite, then concentrated to yield a colorless oil(1.99 g, 40%): R_(f)=0.40 in 1:4 EtOAc:hexanes; ¹H NMR (400 MHz, CDCl₃)δ 7.66-7.55 (m, 1H), 7.25-7.21 (m, 2H), 6.99-6.92 (m, 1H), 6.84-6.79 (m,3H), 6.74-6.71 (m, 1H), 5.54 (s, 1H), 4.22 (q, J=6.8 Hz, 2H), 3.84 (s,3H), 3.30 (d, J=14 Hz, 1H), 3.07 (d, J=14 Hz, 1H), 1.40 (s, 3H), 1.23(t, J=6.8 Hz, 3H).

Step E3-{3-methoxy-4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl-2-methyl-2-phenoxypropionicacid

The title compound was prepared from2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethyl tosylate and3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethylester according to the parallel synthesis procedure (A). MS (EI) 494.4(M+H)⁺.

Example 123-{4-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)-ethoxy]-3-methoxyphenyl}-2-methyl-2-phenoxypropionicacid

The title compound was prepared by Standard Procedure (A), using2-(2-cyclohexyl-5-methyloxazol-4-yl)ethyl tosylate. MS (EI) 494.0(M+H)⁺.

Example 132-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-phenoxy-propionicacid ethyl ester

Step A 3-(4-Allyloxyphenyl)-2-methyl-2-phenoxy-propionic acid ethylester

A solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acidethyl ester (500 mg, 1.67 mmol) in methyl ethyl ketone (6 mL) wastreated with allyl bromide (232 mg, 1.92 mmol, 0.17 mL) and potassiumcarbonate (311 mg, 2.25 mmol) and then heated to reflux. After 18 h, themixture was cooled to ambient temperature and then partitioned betweenEtOAc and water. The aqueous phase was extracted with EtOAc and then theorganic phases were dried (MgSO₄), filtered and concentrated underreduced pressure. The residue was purified by column chromatography (100mL SiO₂, hexanes to 10% EtOAc/hexanes) to provide the desired product(478 mg, 84%) as a clear, colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.22(t, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.97 (dt, J=7.6, 1.2 Hz, 1H),6.83 (d, J=7.8 Hz, 2H), 6.84 (t, J=8.4 Hz, 2H), 6.05 (ddd, J=17.2, 10.6,5.2 Hz, 1H), 5.41 (dd, J=17.2, 1.6 Hz, 1H), 5.28 (dd, J=10.8, 1.4 Hz,1H), 4.22 (d, J=5.2 Hz, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.27 (A of AB, J=14Hz, 1H), 3.11 (B of AB, J=14 Hz, 1H), 1.40 (s, 3H), 1.21 (t, J=6.8 Hz,3H).

Step B 3-(3-Allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acidethyl ester

A solution of 3-(4-allyloxyphenyl)-2-methyl-2-phenoxy-propionic acidethyl ester (475 mg, 1.39 mmol) in dimethylaniline (1.5 mL) was heatedat reflux for 18 h. After cooling to ambient temperature, the reactionmixture was partitioned between EtOAc and 1N H₂SO₄. The organic phasewas dried (MgSO₄), filtered and concentrated. The residue was purifiedby column chromatography (100 mL SiO₂, hexanes to 30% EtOAc/hexanes) toprovide the desired product (343 mg, 72%) as a pale yellow oil: ¹H NMR(400 MHz, CDCl₃) δ 7.23 (t, J=8.4 Hz, 2H), 7.02-6.96 (m, 3H), 6.83 (d,J=8.8 Hz, 2H), 6.72 (d, J=7.6 Hz, 1H), 6.05 (m, 1H), 5.16-5.09 (m, 2H),4.21 (q, J=6.8 Hz, 2H), 3.38 (d, J=6.4 Hz, 2H), 3.25 (A of AB, J=13.6Hz, 1H), 3.10 (B of AB, J=13.6 Hz, 1H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz,3H).

Step C 3-(4-Hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acidethyl ester

A solution of 3-(3-allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (330 mg, 0.97 mmol) in absolute EtOH (5 mL) was treatedwith 5% Pd/C and then the mixture was evacuated three times with N₂. Thereaction mixture was hydrogenated at 1 atm with an H₂-filled balloon for24 h before filtering the mixture over celite and rinsing with EtOH. Theproduct was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ7.22 (t, J=7.6 Hz, 2H), 7.99-6.95 (m, 3H), 6.82 (m, 2H), 6.68 (d, J=8.0Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.24 (A of AB, J=13.6 Hz, 1H), 3.08 (Bof AB, J=13.6 Hz, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.62 (sextet, J=7.6 Hz,2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).

Step D2-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-phenoxy-propionicacid ethyl ester

A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated withcesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester and then heated at 55° C.for 18 h. After cooling to ambient temperature, the mixture waspartitioned between EtOAc and water. The aqueous phase was extractedwith EtOAc and then the organic phases were dried (MgSO₄), filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (100 mL SiO₂, hexanes to 30% EtOAc/hexanes) to providethe desired product (315 mg, 60%) as a clear, colorless oil: MS (EI)528.3 (M+H)⁺.

Step E2-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-phenoxy-propionicacid

A solution of3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester in EtOH (1.5 mL) was treated with 5 N NaOH (140 μL) andthen warmed to 65° C. After 18 h, the mixture was acidified to pH=1 with5 N HCl. The mixture was extracted with EtOAc and then the combinedorganic phases were dried (MgSO₄), filtered and concentrated underreduced pressure to yield the title product. MS (EI) 500.2 (M+H)⁺; LCRT=3.22 min (>99% pure).

Example 143-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound, and its corresponding ester: MS (EI) 534.3 (M+H)⁺shown below, were synthesized according to the procedure of Example 13,Steps D and E, respectively from toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester, and then purified byLC/MS: MS (EI) 506.2 (M+H)⁺; LC RT=3.11 min (>85% pure).

Example 152-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-phenoxy-propionicacid

The title compound, and its corresponding ester: MS (EI) 534.2 (M+H)⁺shown below, were synthesized according to the procedure of Example 13,Steps D and E, respectively from toluene-4-sulfonic acid2-(5-methyl-2-thiophen-5-methyl-oxazol-4-yl)-ethyl ester, and thenpurified by LC/MS: MS (EI) 506.1 (M+H)⁺; LC RT=3.12 min (>99% pure).

Example 163-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid

Step A 2-(4-tert-Butyl-phenoxy)-propionic acid ethyl ester

4-t-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was addeddropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. underan atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultantmixture was allowed to stir for 18 h, gradually warming to ambienttemperature. The reaction mixture was diluted with ethyl acetate (300mL) and extracted twice with water and once with brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to produce acolorless oil (12.5 g, 100%) ¹H NMR (300 MHz, CDCl₃): δ 7.28 (d, 2H,J=5.5), 6.80 (d, 2H, J=5.5), 4.70 (q, 1H, J=6.6), 4.22 (q, 2H, J=7.1),1.59 (d, 3H, J=6.6), 1.28 (s, 9H), 1.25 (t, 3H, J=7.1). MS [EI+] 251(M+H)⁺, 268 (M+NH₄)⁺.

Step B 2-(4-tert-Butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionicacid ethyl ester

A solution of LDA (12.7 mL, 19.1 mmol, 1.5 M in cyclohexane) was cooledto −78° C. in a dry ice/acetone bath and then added to a solution of2-(4-tert-butyl-phenoxy)-propionic acid ethyl ester in anhydrous THF (20mL) also cooled to −78° C. under an atmosphere of nitrogen. After fivemin, 4-benzyloxybenzaldehyde (3.69 g, 17.4 mmol) was added in oneportion. After stirring for 10 min, the reaction mixture was quenchedwith saturated solution of aqueous NH₄Cl (10 mL) and the mixture allowedto warm to ambient temperature. The biphasic mixture was diluted withether (100 mL) and partitioned, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (600 g silica, 25×200 mLfractions, gradient elution 0-20% ethyl acetate in hexanes) to provide acolorless oil (3.46 g, 58%) as a mixture of inseparable diastereomers of3-(4-benzyloxyphenyl)-2-(4-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification.

3-(4-Benzyloxy-phenyl)-2-(4-tert-butyl-phenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester (3.46 g, 7.5 mmol) in anhydrous CH₂Cl₂ (50 mL) wascooled to 0° C. and treated with pyridine (6.0 mL, 75 mmol, d=0.978).Trifluoroacetic anhydride (2.11 mL, 15 mmol, d=1.487) was added dropwiseand the mixture was stirred for 1 h, gradually warming to ambienttemperature. The solution was washed twice with 1N HCl and the organiclayer dried over Na₂SO₄ and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-tert-butyl-phenoxy)-3-trifluoroacetoxy-2-methylpropionicacid ethyl ester which was used without characterization.

The material was dissolved in ethyl acetate (50 mL) and treated with 10%palladium on carbon (1.5 g), and stirred under an atmosphere of hydrogenfor 48 h. The suspension was filtered through celite and concentrated invacuo to a golden oil. The residue was purified by flash columnchromatography (200 g silica, 30×20 mL fractions, 2% ethyl acetate inCHCl₃) to provide the title compound as a colorless oil (1.06 g, twosteps 40%) ¹H NMR (300 MHz, CDCl₃): δ 7.21 (d, 2H, J=8.6), 7.12 (d, 2H,J=8.6), 4.19 (q, 1H, J=7.1), 3.24 (d, 1H, J=12.3), 3.11 (d, 1H, J=12.3),1.38 (s, 3H), 1.27 (s, 9H), 1.23 (t, J=7.1). MS [EI+] 357 (M+H)⁺, [EI−]355 (M−H)⁺.

Step C3-{4-[2-(2-Phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-tert-butylphenoxy)-propionicacid

The title compound was prepared using the representative StandardProcedure (A) from3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-phenyl)-oxazol-4-yl)-ethyl ester to produce a white solid(17%). MS [EI+] 514 (M+H)⁺, [EI−] 512 (M−H)⁺.

Example 172-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-tert-butylphenoxy)-propionicacid

The title compound was prepared, according to the procedure of Example16, Step C, using3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yloxazol-4-yl)-ethyl ester to produce a whitesolid (19%). MS [EI+] 520 (M+H)⁺, [EI−] 518 (M−H)⁺.

Example 182-Methyl-3-(4-{2-[5-methyl-2-cyclohexylyl-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-tert-butylphenoxy)-propionicacid

The title compound was prepared, according to the procedure of Example16, Step C, using3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-cyclohexylyl-oxazol-4-yl)-ethyl ester to produce a whitesolid (18%). MS [EI+] 520 (M+H)⁺, [EI−] 518 (M−H)⁺.

Example 192-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid

Step A 2-(4-Methoxyphenoxy)-propionic acid ethyl ester

4-Methoxyphenol (3.29 g, 26.5 mmol), K₂CO₃ (7.32 g, 53 mmol), and ethyl2-bromopropionate (4.8 g, 26.5 mmol) were combined in anhydrous DMF (50mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h,the DMF was removed in vacuo. The residue was dissolved in ethyl acetate(100 mL) and washed twice with water and once with brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to produce agolden oil (4.8 g, 81%) ¹H NMR (250 MHz, CDCl₃): δ 6.76 (d, 2H, J=7.9),6.73 (d, 2H, J=7.9), 4.58 (q, 1H, J=6.1), 4.14 (q, 2H, J=7.2), 3.69 (s,3H), 1.52 (d, 3H, J=6.1), 1.19 (t, 3H, J=7.2). MS [EI+] 225 (M+H)⁺,[EI−] 223 (M−H)⁺.

Step B 2-(4-Methoxyphenoxy)-3-(4-benzyloxyphenyl)-2-methylpropionic acidethyl ester

A solution of 2-(4-methoxyphenoxy)-propionic acid ethyl ester inanhydrous THF (20 mL) was cooled to −78° C. under nitrogen and thentreated with dropwise addition of LDA (13.4 mL, 20 mmol, 1.5M incyclohexane) at a rate slow enough to keep the temperature below −70° C.After 30 min, 4-benzyloxybenzaldehyde (3.88 g, 18.3 mmol) in anhydrousTHF was added slowly dropwise in the fashion previously described. Afterstirring for 30 min, the reaction mixture was quenched with saturatedsolution of aqueous NH₄Cl (20 mL) and the mixture was warmed to ambienttemperature. The biphasic mixture was diluted with ether (100 mL) andpartitioned, and the organic layer was washed with brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography (500 g silica, 40×125 mL fractions, gradientelution 0-20% ethyl acetate in hexanes) to provide a colorless oil (3.97g, 50%) as a mixture of inseparable diastereomers of3-(4-benzyloxy-phenyl)-2-(4-methoxyphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester which was used without further characterization orpurification. R_(f)=0.28 in 4:1 hexanes:ethyl acetate.

3-(4-Benzyloxyphenyl)-2-(4-methoxyphenoxy)-3-hydroxy-2-methylpropionicacid ethyl ester (2.15 g, 4.9 mmol) in anhydrous CH₂Cl₂ (30 mL) wascooled to 0° C. and treated with BF₃-Et₂O (0.91 mL, 7.4 mmol, d=1.154)and triethylsilane (1.18 mL, 7.4 mmol, d=0.728). The mixture was stirredfor 2 h, gradually warming to ambient temperature. Saturated aqueousNa₂CO₃ (15 mL) was added and the mixture was stirred vigorously. Thesolution was partitioned and the organic layer was washed twice withwater and brine, dried over Na₂SO₄, and concentrated in vacuo to produce3-(4-benzyloxyphenyl)-2-(4-methoxyphenoxy)-2-methylpropionic acid ethylester as a colorless oil (428 mg, 21%). R_(f)=0.36 in 4:1 hexanes:ethylacetate ¹H NMR (300 MHz, CDCl₃): δ 7.45 (t, 2H, J=7.1), 7.35 (d, 2H,J=7.1), 7.34 (t, 1H, J=7.0), 7.18 (d, 2H, 8.6), 6.91 (d, 2H, J=6.6),6.79 (d, 2H, 8.6), 6.74 (d, 2H, J=6.6), 5.05 (s, 2H), 4.21 (q, 1H,J=7.1), 3.75 (s, 3H), 3.23 (d, 1H, J=13.7), 3.10 (d, 1H, J=13.7), 1.31(s, 3H), 1.25 (t, 3H, J=7.1). MS [EI+] 438 (M+NH₄)⁺, [EI−] 419 (M−H)⁺.

Step C 2-(4-Methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester

3-(4-Benzyloxy-phenyl)-2-(4-methoxyphenoxy)-2-methylpropionic acid ethylester (428 mg, 1.0 mmol) was dissolved in ethanol (50 mL) and treatedwith 5% palladium on carbon (200 mg), and stirred under an atmosphere ofhydrogen for 16 h. The suspension was filtered through celite andconcentrated in vacuo to provide a colorless oil. (257 mg, 76%) ¹H NMR(300 MHz, CDCl₃): δ 7.06 (d, 2H, J=8.6), 6.73 (d, 2H, J=6.6), 6.72 (d,2H, J=8.6), 6.69 (t, 1H, J=6.6), 4.16 (q, 1H, J=7.4), 3.68 (s, 3H), 3.14(d, 1H, J=13.7), 3.01 (d, 1H, J=13.7), 1.23 (s, 3H), 1.18 (t, J=7.4). MS[EI+1331 (M+H)⁺, 348 (M+NH₄)⁺, [EI−] 329 (M−H)⁺.

2-(4-Methoxyphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester (515821) (approx. 2.5 g) prepared in the same manner was purifiedby chiral chromatography to provide the individual enantiomers (ChiracelOD, 8×29 cm, 5% IPA/heptane, 275 nm; (S)-isomer: 1.09 g, 97.4% ee,(R)-isomer: 1.01 g, >99% ee).

Step D2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid ethyl ester

Prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-methoxyphenoxy)-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce acolorless oil (86%). ¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, 1H, J=3.5),7.36 (d, 1H, J=5.1), 7.15 (d, 2H, J=8.6), 7.07 (dd, 1H, J=5.1, 3.5),6.81 (d, 2H, J=6.6), 6.78 (d, 2H, J=8.6), 6.71 (d, 2H, J=6.6), 4.21 (q,2H, J=7.2), 4.20 (t, 2H, J=6.4), 3.74 (s, 3H), 3.21 (d, 1H, J=13.7),3.08 (d, 1H, J=13.7), 2.95 (t, 2H, J=6.4), 2.35 (s, 3H), 1.28 (s, 3H),1.25 (t, 3H, J=7.2). MS [EI+] 522 (M+H)⁺.

Step E2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid

The title compound was prepared from2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid ethyl ester using the hydrolysis procedure of Example 1, Step E, toprovide a white solid (63%). ¹H NMR (300 MHz, d₆-DMSO): δ 7.70 (d, 1H,J=4.8), 7.57 (d, 1H, J=3.9), 7.15 (dd, 1H, J=4.8, 3.9), 7.10 (d, 2H,J=8.6), 6.83 (d, 2H, J=8.6), 6.76 (d, 2H, J=9.0), 6.71 (d, 2H, J=9.0),4.12 (t, 2H, J=6.4), 3.65 (s, 3H), 3.07 (d, 1H, J=13.7), 3.06 (d, 1H,J=13.7), 2.86 (t, 2H, J=6.4), 2.30 (s, 3H), 1.20 (s, 3H). MS [EI+] 494(M+H)⁺, [EI−] 492 (M−H).

Example 20(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid

Step A(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid ethyl ester

The title compound was prepared from(S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-methoxyphenoxy)-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce acolorless oil (32%). ¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, 1H, J=3.5),7.36 (d, 1H, J=5.1), 7.15 (d, 2H, J=8.6), 7.07 (dd, 1H, J=5.1, 3.5),6.81 (d, 2H, J=6.6), 6.78 (d, 2H, J=8.6), 6.71 (d, 2H, J=6.6), 4.21 (q,2H, J=7.2), 4.20 (t, 2H, J=6.4), 3.74 (s, 3H), 3.21 (d, 1H, J=13.7),3.08 (d, 1H, J=13.7), 2.95 (t, 2H, J=6.4), 2.35 (s, 3H), 1.28 (s, 3H),1.25 (t, 3H, J=7.2). MS [EI+] 522 (M+H)⁺.

Step B(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid

The title compound was prepared from(S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-methoxyphenoxy)-propionicacid ethyl ester, according to the procedure of Example 19, Step E, toprovide a sticky white solid (83%). ¹H NMR (300 MHz, d₆-DMSO): δ 7.70(d, 1H, J=4.8), 7.57 (d, 1H, J=3.9), 7.15 (dd, 1H, J=4.8, 3.9), 7.10 (d,2H, J=8.6), 6.83 (d, 2H, J=8.6), 6.76 (d, 2H, J=9.0), 6.71 (d, 2H,J=9.0), 4.12 (t, 2H, J=6.4), 3.65 (s, 3H), 3.07 (d, 1H, J=13.7), 3.06(d, 1H, J=13.7), 2.86 (t, 2H, J=6.4), 2.30 (s, 3H), 1.20 (s, 3H). MS[EI+] 494 (M+H)⁺, [EI−] 492 (M−H).

Example 212-(3-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

2-(3-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid was obtained from2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester by the Standard Procedure (B). ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.97(m, 2H), 7.47-7.45 (m, 3H), 7.21-7.15 (m, 3H), 6.82 (d, 2H, J=8.2 Hz),6.76-6.61 (m, 3H), 4.20 (t, 2H, J=6.3 Hz), 3.26 (d, 1H, J=14.1 Hz), 3.12(d, 1H, J=14.1 Hz), 3.05 (t, 2H, J=6.3 Hz), 2.42 (s, 3H), 1.44 (s, 3H).HRMS (ES⁺) m/z exact mass calcd for C₂₈H₂₆FNO₅ 476.1873, found 476.1869.

Example 222-(3-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(3-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester according to themethod of Example 21. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (dd, 1H, J=3.5 Hz,1.17 Hz), 7.41 (dd, 1H, J=5.1 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08 (dd,1H, J=5.1 Hz, 3.91 Hz), 6.81 (d, 2H, J=8.6 Hz), 6.75-6.62 (m, 3H), 4.17(t, 2H, J=6.6 Hz), 3.26 (d, 1H, J=13.7 Hz), 3.14 (d, 1H, J=13.69 Hz),2.98 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 1.45 (s, 3H). HRMS (ES⁺) m/zexact mass calcd for C₂₆H₂₅FNO₅S 482.1437, found 482.1454.

Example 232-(3-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-cyclohexyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester according to the methodof Example 21.

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.8Hz), 7.50-7.27 (m, 5H), 7.12 (m, 3H), 6.76 (d, 2H, J=8.6 Hz), 6.72-6.58(m, 3H), 4.14 (t, 2H, J=6.7 Hz), 3.18 (d, 1H, J=14.1 Hz), 3.08 (d, 1H,J=14.1 Hz), 2.94 (t, 2H, J=6.7 Hz), 2.37 (s, 3H), 1.38 (s, 3H). MS (ES⁺)m/z mass calcd for C₃₄H₃₁FNO₅ 552.21, found 552.2.

Example 242-(3-tert-Butyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

2-(3-t-Butyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-propionicacid was obtained from2-(3-tert-butyl-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester by the Standard Procedure (B). ¹H NMR (400 MHz, CDCl₃) δ7.19-7.16 (m, 3H), 7.08 (dt, 1H, J=7.0 Hz, 0.8 Hz), 7.92 (t, 1H, J=2.0Hz), 6.83 (d, 2H, J=8.6 Hz), 6.72-6.99 (m, 1H), 4.21 (t, 2H, J=6.3 Hz),3.25 (d, 1H, J=14.1 Hz), 3.15 (d, 1H, J=14.1 Hz), 3.00 (t, 2H, J=6.3Hz), 2.39 (s, 3H), 1.43 (s, 3H), 1.25 (s, 9H). HRMS (ES⁺) m/z exact masscalcd for C₃₂H₃₅₄NO₅ 514.2593, found 514.2622.

Example 252-(3-tert-Butyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(3-tert-butyl-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure ofExample 24. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd, 1H, J=3.91 Hz, 1.17 Hz),7.37 (dd, 1H, J=5.09 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08-7.06 (m, 2H),6.89 (t, 1H, J=2.35 Hz), 6.82 (d, 2H, J=8.60 Hz), 6.71 (dd, 1H, J=8.60Hz, 2.74 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15(d, 1H, J=14.08 Hz), 2.96 (t, 2H, J=6.26 Hz), 2.35 (s, 3H), 1.43 (s,3H), 1.26 (s, 9H). HRMS (ES⁺) m/z exact mass calcd for C₃₀H₃₄NO₅S520.2157, found 520.2182.

Example 262-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

2-(2-Fluorophenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid was prepared from2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester by the parallel synthesis method (B). ¹H NMR (400 MHz, CDCl₃) δ7.96 (dd, 2H, J=7.43 Hz, 2.35 Hz), 7.42-7.40 (m, 3H), 7.22 (d, 2H,J=8.99 Hz), 7.12-6.95 (m, 4H), 6.84 (d, 2H, J=8.60 Hz), 4.20 (t, 2H,J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.99 (t,2H, J=6.65 Hz), 2.38 (s, 3H), 1.42 (s, 3H). HRMS (ES⁺) m/z exact masscalcd for C₂₈H₂₆FNO₅ 476.1873, found 476.1858.

Example 272-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure ofExample 26. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, 1H, J=3.52 Hz, 1.17 Hz),7.36 (dd, 1H, J=5.08 Hz, 1.17 Hz), 7.21 (d, 3H, J=8.60 Hz), 7.12-6.95(m, 3H), 6.83 (d, 3H, J=8.60 Hz), 4.19 (t, 2H, J=6.65 Hz), 3.27 (d, 1H,J=14.08 Hz), 3.17 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.65 Hz), 2.35 (s,3H), 1.41 (s, 3H). HRMS (ES⁺) m/z exact mass calcd for C₂₆H₂₅FNO₅S482.1437, found 482.1454.

Example 283-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

The title compound was prepared from2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure ofExample 26. ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, 2H, J=8.60 Hz), 7.12-6.96(m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.15 (t, 2H, J=6.65 Hz), 3.26 (d, 1H,J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.98-2.80 (m, 2H), 2.32 (s, 3H),2.02 (d, 2H, J=10.95 Hz), 1.81 (d, 2H, J=12.90 Hz), 1.70 (d, 1H, J=12.90Hz), 1.85 (q, 2H, J=11.73 Hz), 1.40 (s, 3H), 1.39-1.23 (m, 3H). HRMS(ES⁺) m/z exact mass calcd for C₂₈H₃₃FNO₅ 482.2343, found 482.2349.

Example 292-(4-Chloro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

2-(4-Chlorophenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid was obtained from2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester by the Standard Procedure (B). ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.96(m, 2H), 7.45 (d, 3H, J=6.65 Hz), 7.17 (t, 4H, J=7.43 Hz), 6.82 (dd, 4H,J=8.60 Hz, 2.74 Hz), 4.20 (t, 2H, J=6.26 Hz), 3.23 (d, 1H, J=14.08 Hz),3.12 (d, 1H, J=14.08 Hz), 3.04 (t, 2H, J=6.26 Hz), 2.41 (s, 3H), 1.39(s, 3H). MS (ES⁺) m/z mass calcd for C₂₈H₂₇ClNO₅ 492.16, found 492.2.

Example 302-(4-Chlorophenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure ofExample 29. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, 1H, J=4.30 Hz), 7.38 (d,1H, J=4.30 Hz), 7.20-7.16 (m, 4H), 7.06 (dd, 1H, J=8.60 Hz, 3.91 Hz),6.83 (t, 4H, J=8.60 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.23 (d, 1H, J=14.08Hz), 3.14 (d, 1H, J=14.08 Hz), 2.97 (t, 2H, J=6.65 Hz), 2.36 (s, 3H),1.41 (s, 3H). MS (ES⁺) m/z mass calcd for C₂₆H₂₅ClNO₅S 498.12, found498.1.

Example 312-(4-Chlorophenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

The title compound was prepared from2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure ofExample 29. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, 2H, J=8.60 Hz), 7.16 (d,2H, J=8.60 Hz), 6.83 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 4.12(t, 2H, J=6.26 Hz), 3.21 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz),2.95 (t, 2H, J=6.26 Hz), 2.89-2.83 (m, 3H), 2.05 (d, 2H, J=11.73 Hz),1.80 (d, 2H, J=11.73 Hz), 1.55 (q, 2H, J=11.73 Hz), 1.40 (s, 3H),1.37-1.20 (m, 4H). MS (ES⁺) m/z mass calcd for C₂₈H₃₃ClNO₅ 498.21, found498.2.

Example 322-(4-Cyclohexyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

2-(4-Cyclohexyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid was obtained from2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester by the Standard Procedure (B). ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.98(m, 2H), 7.45 (t, 3H, J=2.80 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.08 (d, 2H,J=7.90 Hz), 6.82 (d, 4H, J=8.60 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.22 (d,1H, J=14.08 Hz), 3.12 (d, 1H, J=14.08 Hz), 2.40 (s, 4H), 1.83-1.71 (m,5H), 1.40 (s, 3H), 1.38-1.16 (m, 6H). MS (ES⁺) m/z mass calcd forC₃₄H₃₈NO₅ 540.28, found 540.3.

Example 332-(4-Cyclohexyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester by the method of Example 32. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d,1H, J=3.13 Hz), 7.43 (dd, 1H, J=4.69 Hz, 0.78 Hz), 7.18 (d, 2H, J=8.60Hz), 7.10 (dd, 1H, J=5.08 Hz, 3.52 Hz), 7.08 (d, 2H, J=8.60 Hz),6.87-6.80 (m, 4H), 4.19 (t, 2H, J=6.26 Hz), 3.39 (s, 5H), 3.23 (d, 1H,J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.26 Hz), 2.37 (s,3H), 1.82 (d, 4H, J=11.73 Hz), 1.73 (d, 1H, J=11.73 Hz), 1.40 (s, 3H).MS (ES⁺) m/z mass calcd for C₃₂H₃₆NO₅S 546.23, found 546.2.

Example 343-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionicacid

The title compound was prepared from2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester by the method of Example 32. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d,2H, J=8.60 Hz), 7.08 (d, 2H, J=8.60 Hz), 6.80 (q, 4H, J=8.60 Hz), 4.14(t, 2H, J=6.26 Hz), 3.38 (s, 6H), 3.22 (d, 1H, J=14.08 Hz), 3.12 (d, 1H,J=14.08 Hz), 2.96 (t, 2H, J=6.26 Hz), 2.92-2.83 (m, 2H), 2.30 (s, 3H),2.02 (d, 2H, J=10.56), 1.81-1.78 (m, 6H), 1.76-1.68 (m, 2H), 1.59-1.50(m, 2H), 1.40 (s, 3H). MS (ES⁺) m/z mass calcd for C₃₄H₄₄NO₅ 546.32,found 546.3.

Example 353-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionicacid

The representative parallel synthesis procedure (B) was used to preparethe title compound from2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃) δ 7.18 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.79 (d, 2H,J=8.4 Hz), 6.71 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4, 2.4 Hz), 4.16(t, 2H, J=6.0 Hz), 3.21 and 3.11 (d of Abq, 2H, J=14.0 Hz), 2.98 (t, 2H,J=6.0 Hz), 2.91 (tt, 1H, J=11.4, 3.2 Hz), 2.31 (s, 3H), 2.20 (s, 3H),2.19 (s, 3H), 2.06-2.02 (m, 2H), 1.85-1.79 (m, 2H), 1.73-1.68 (m, 1H),1.62-1.51 (m, 2H), 1.42-1.22 (m, 3H), 1.39 (s, 3H). IR (KBr) 3500, 2935,1735, 1612, 1513, 1249, 1178 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd forC₃₀H₃₈NO₅ 492.2750, found 492.2751.

Example 362-(3,4-Dimethyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The procedure of Example 35 was used to prepare the title compound from2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thipohen-2-yl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃) δ 7.73 (d, 1H, J=3.2 Hz), 7.46 (d, 1H, J=4.8 Hz), 7.18 (d, 2H,J=8.4 Hz), 7.13-7.10 (m, 1H), 7.06 (bs, 1H), 6.99 (d, 1H, J=8.0 Hz),6.81 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.4 Hz), 6.63 (dd, 1H, J=8.0, 2.4Hz), 4.20 (t, 2H, J=6.0 Hz), 3.23 and 3.11 (d of Abq, 2H, J=14.0 Hz),3.02 (t, 2H, J=6.0 Hz), 2.38 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39(s, 3H). IR (KBr) 3500, 3000, 1729, 1512, 1250, 1178 cm⁻¹. HRMS (ES⁺)m/z exact mass calcd for C₂₈H₃₀NO₅S 492.1845, found 492.1845.

Example 372-(3,4-Dimethyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The representative parallel synthesis procedure (B) was used to preparethe title compound from2-(3,4-dimethyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acidethyl ester and toluene-4-sulfonic acid2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ8.01-7.99 (m, 2H), 7.48-7.46 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 6.99 (d,1H, J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.0 Hz), 6.63 (dd,1H, J=8.4, 2.0 Hz), 6.28 (bs, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.22 and 3.11(d of Abq, 2H, J=13.6 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 2.19(s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3100, 2950, 1772, 1611,1512, 1177 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₃₀H₃₂NO₅ 486.2280,found 486.2295.

Example 382-(3,4-Dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

The representative parallel synthesis procedure (B) was used to preparethe title compound from2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethylester and toluene-4-sulfonic acid2-(S-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester. ¹H NMR (400MHz, CDCl₃) δ 7.10 (d, 2H, J=8.60 Hz), 6.92 (d, 1H, J=8.60 Hz), 6.73 (d,2H, J=8.99 Hz), 6.64 (d, 1H, J=2.35 Hz), 6.57 (dd, 1H, J=8.21 Hz, J=3.13Hz), 4.06 (t, 2H, J=6.25 Hz), 3.14 (d, 1H, J=14.08 Hz), 3.04 (d, 1H,J=14.08 Hz), 2.85 (t, 2H, J=6.25 Hz), 2.19 (s, 3H), 2.13 (s, 3H), 2.12(s, 3H), 2.07-2.01 (m, 2H), 1.53-1.28 (m, 8H), 1.36 (s, 3H), 1.20 (s,3H); MS (ES⁺) calcd for C₃₁H₄₀NO₅: Found m/e 506.3 (M+1, 100%).

Example 392-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-p-tolyloxy-propionicacid

The representative procedure (B) was utilized to prepare the titlecompound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acidethyl ester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ8.05 (bs, 1H), 8.02-7.96 (m, 2H), 7.51-7.45 (m, 3H), 7.18 (d, 2H, J=8.4Hz), 7.05 (d, 2H, J=8.4 Hz), 6.81 and 6.81 (d of Abq, 4H, J=8.0 Hz),4.22 (t, 2H, J=6.0 Hz), 3.23 and 3.11 (d of Abq, 2H, J=14.0 Hz), 3.06(t, 2H, J=6.0 Hz), 2.42 (s, 3H), 2.28 (s, 3H), 1.38 (s, 3H). IR (KBr)3420, 1718, 1712, 1508, 1228 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd forC₂₉H₃₀NO₅ 472.2124, found 474.2139.

Example 402-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-p-tolyloxy-propionicacid

The representative procedure (B) was utilized to prepare the titlecompound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃) δ 10.0 (bs, 1H), 7.59 (dd, 1H, J=3.8, 1.2 Hz), 7.36 (dd, 1H,J=5.0, 1.2 Hz), 7.19 (d, 2H, J=8.4 Hz), 7.05 (dd, 1H, J=5.0, 3.8 Hz),7.02 (d, 2H, J=8.0 Hz), 6.83-6.80 (m, 4H), 4.17 (t, 2H, J=6.4 Hz), 3.29and 3.14 (d of Abq, 2H, J=13.8 Hz), 2.96 (t, 2H, J=6.4 Hz), 2.35 (s,3H), 2.27 (s, 3H), 1.38 (s, 3H). IR (KBr) 3420, 1715, 1509, 1225 cm⁻¹.HRMS (ES⁺) m/z exact mass calcd for C₂₇H₂₈NO₅S 478.1688, found 478.1714.

Example 413-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

The representative procedure (B) was utilized to prepare the titlecompound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acidethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃) δ 10.90 (bs, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.05 (d, 2H, J=8.4 Hz),6.79 and 6.79 (d of Abq, 4H, J=8.0 Hz), 4.15 (t, 2H, J=6.0 Hz), 3.23 and3.11 (d of Abq, 2H, J=13.8 Hz), 3.02-2.93 (m, 3H), 2.34 (s, 3H), 2.29(s, 3H), 2.10-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.77-1.70 (m, 1H),1.64-1.51 (m, 2H), 1.45-1.19 (m, 3H), 1.38 (s, 3H). IR (KBr) 3450, 1734,1509, 1228 cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₆NO₅ 478.2593,found 478.2613.

The following compounds were prepared from(S)-3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester(96% ee, Chiracel OD separation, 8×29 cm, 7% IPA/heptane, 275 nm) by theprocedure described in Example 1:(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-p-tolyloxy-propionicacid and(S)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid.

Example 422-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethoxy-phenoxy)-propionicacid

The representative procedure (B) was utilized to prepare the titlecompound from3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃) δ 7.79-7.94 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.8 Hz),7.07 (d, 2H, J=8.4 Hz), 6.89 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.4 Hz),4.19 (t, 2H, J=6.4 Hz), 3.24 and 3.14 (d of Abq, 2H, J=14.0 Hz), 3.01(t, 2H, J=6.4 Hz), 3.00 (bs, 1H), 2.39 (s, 3H), 1.42 (s, 3H). IR (KBr)3600, 2980, 1725, 1611, 1504, 1265 cm⁻¹. HRMS (ES⁺) m/z exact mass calcdfor C₂₉H₂₇NO₆F₃ 542.1790, found 542.1802.

Example 432-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethoxy-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedureof Example 42. ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.67 (m, 1H), 7.41 (dd,1H, J=5.2, 1.2 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.11-7.07 (m, 3H), 6.90 (d,2H, J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.20 (t, 2H, J=6.6 Hz), 3.25 and3.14 (d of Abq, 2H, J=14.0 Hz), 2.99 (t, 2H, J=6.4 Hz), 2.37 (s, 3H),1.43 (s, 3H). IR (KBr) 3600, 3000, 1727, 1611, 1504, 1265 cm⁻¹. HRMS(ES⁺) m/z exact mass calcd for C₂₇H₂₅NO₆F₃S 548.1354, found 548.1362.

Example 443-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure ofExample 42. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, 2H, J=8.4 Hz), 7.13 (d,2H, J=8.4 Hz), 6.90 (d, 2H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 4.43 (bs,1H), 4.16 (t, 2H, J=6.0 Hz), 3.25 and 3.13 (d of Abq, 2H, J=14.0 Hz),3.02 (t, 2H, J=6.0 Hz), 3.02-2.98 (m, 1H), 2.36 (s, 3H), 2.09-2.00 (m,2H), 1.88-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.64-1.52 (m, 2H), 1.43 (s,3H), 1.40-1.23 (m, 3H). IR (KBr) 3600, 2980, 1725, 1601, 1500, 1268cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₃NO₆F₃ 548.2260, found548.2274.

Example 452-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using theprocedure of Example 42. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, 2H, J=8.60Hz), 7.08 (d, 2H, J=8.60 Hz), 6.89 (d, 2H, J=8.60 Hz), 6.79 (d, 2H,J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.11 (d,1H, J=14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.16-2.08 (m,2H), 1.62-1.32 (m, 8H), 1.42 (s, 3H), 1.32 (s, 3H); MS (ES⁺) calcd forC₃₀H₃₅NO₆F₃: Found m/e 562.3 (M+1, 100%).

Example 462-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

The Standard Procedure (B) was utilized to prepare the title compoundfrom 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester andtoluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.¹H NMR (400 MHz, CDCl₃) δ 7.99-7.94 (m, 2H), 7.44-7.40 (m, 3H),7.32-7.28 (m, 2H), 7.07 (t, 1H, J=7.4 Hz), 7.02-6.97 (m, 4H), 6.79-6.74(m, 2H), 4.18 (t, 2H, J=6.6 Hz), 3.29 (s, 2H), 2.98 (t, 2H, J=6.6 Hz),2.37 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6Hz), 0.91 (t, 3H, J=7.6 Hz).

Example 472-{4-[2-(5-Methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester andtoluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethylester using the method of Example 46. ¹H NMR (400 MHz, CDCl₃) δ 7.59(dd, 1H, J=3.6, 0.8 Hz), 7.37 (dd, 1H, J=5.2, 1.2 Hz), 7.33-7.27 (m,2H), 7.09-7.05 (m, 2H), 7.02-6.96 (m, 4H), 6.78-6.73 (m, 2H), 4.16 (t,2H, J=6.6 Hz), 3.29 (s, 2H), 2.94 (t, 2H, J=6.6 Hz), 2.34 (s, 3H), 2.14(qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H,J=7.6 Hz).

Example 482-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyricacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester andtoluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethylester using the method of Example 46. ¹H NMR (400 MHz, CDCl₃) δ 8.01(bs, 1H), 7.31-7.26 (m, 2H), 7.06-6.96 (m, 5H), 6.72 (d, 2H, J=8.8 Hz),4.08 (t, 2H, J=6.4 Hz), 3.28 (s, 2H), 2.91 (t, 2H, J=6.4 Hz), 2.81 (tt,1H, J=11.6, 3.6 Hz), 2.26 (s, 3H), 2.18-1.98 (m, 4H), 1.82-1.77 (m, 2H),1.72-1.67 (m, 1H), 1.58-1.48 (m, 2H), 1.39-1.18 (m, 3H), 0.92 (t, 3H,J=7.6 Hz).

Example 492-(4-{2-[5-Methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester andtoluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using themethod of Example 46. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (dd, 2H, J=8.60 Hz,J=7.43 Hz), 7.07-7.03 (m, 1H), 7.02-6.96 (m, 4H), 6.72 (d, 2H, J=8.60Hz), 4.10 (t, 2H, J=6.25 Hz), 2.38 (s, 2H), 2.95 (t, 2H, J=6.25 Hz),2.29 (s, 3H), 2.15-2.01 (m, 4H), 1.56-1.36 (m, 8H), 1.30 (s, 3H), 0.91(t, 3H, J=7.43 Hz); MS (ES⁺) calcd for C₃₀H₃₈NO₅: Found m/e 492.3 (M+1,100%).

Example 502-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 9.18 (bs, 1H), 7.96 (d, 2H,J=6.8 Hz), 7.52-7.40 (m, 5H), 7.16 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.8Hz), 6.80 (d, 2H, J=8.4 Hz), 4.18 (t, 2H, J=6.0 Hz), 3.28 and 3.15 (d ofAbq, 2H, J=14.0 Hz), 3.05 (t, 2H, J=6.0 Hz), 2.42 (s, 3H), 1.47 (s, 3H).IR (KBr) 3420, 1734, 1613, 1513, 1328 cm⁻¹. HRMS (ES⁺) m/z exact masscalcd for C₂₉H₂₇NO₅F₃ 526.1841, found 526.1851.

Example 512-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedureof Example 50. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (bs, 1H), 7.66 (d, 1H,J=3.2 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.43 (d, 1H, J=5.0 Hz), 7.16 (d, 2H,J=8.4 Hz), 7.08 (dd, 1H, J=5.0, 3.2 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.80(d, 2H, J=8.4 Hz), 4.16 (t, 2H, J=6.2 Hz), 3.28 and 3.16 (d of Abq, 2H,J=13.8 Hz), 3.00 (t, 2H, J=6.2 Hz), 2.37 (s, 3H), 1.49 (s, 3H). IR (KBr)3420, 3000, 1714, 1614, 1513, 1327 cm⁻¹. HRMS (ES⁺) m/z exact mass calcdfor C₂₇H₂₅NO₅F₃S 532.1406, found 532.1412.

Example 523-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)propionic acidethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure ofExample 50. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, 2H, J=8.8 Hz), 7.16 (d,2H, J=8.8 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.4 Hz), 4.11 (t,2H, J=6.2 Hz), 3.24 and 3.15 (d of ABq, 2H, J=13.8 Hz), 2.95 (t, 2H,J=6.2 Hz), 2.85 (tt, 1H, J=11.6, 3.4 Hz), 2.30 (s, 3H), 2.03-1.95 (m,2H), 1.83-1.74 (m, 2H), 1.73-1.68 (m, 1H), 1.58-1.47 (m, 1H), 1.49 (s,3H), 1.38-1.17 (m, 4H). IR (KBr) 3400, 2937, 1735, 1614, 1513, 1328cm⁻¹. HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₃NO₅F₃ 532.2311, found532.2332.

Example 532-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using theprocedure of Example 50. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, 2H, J=8.60Hz), 7.15 (d, 2H, J=8.60 Hz), 6.94 (d, 2H, J=8.60 Hz), 6.78 (d, 2H,J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d,1H, J 14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.14-2.06 (m,2H), 1.61-1.41 (m, 8H), 1.49 (s, 3H), 1.30 (s, 3H); MS (ES⁺) calcd forC₃₀H₃₅NO₅F₃: Found m/e 546.3 (M+1, 100%).

Example 54(S)-3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from(S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester (95% ee; Chiralpak AD separation, 8×27 cm, 10%IPA/heptane, 275 nm) and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the proceduredescribed in Example 1.

Example 55(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from(S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester (95% ee; Chiralpak AD separation, 8×27 cm, 10%IPA/heptane, 275 nm) and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the proceduredescribed in Example 1.

Example 562-(3,4-Difluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

Standard Procedure (B) was utilized to prepare2-(3,4-difluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid from2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 9.13 (bs, 1H), 7.99-7.95 (m, 2H),7.48-7.41 (m, 3H), 7.17 (d, 2H, J=8.4 Hz), 6.99 (q, 1H, J=9.5 Hz), 6.82(d, 2H, J=8.4 Hz), 6.75 (ddd, 1H, J=11.6, 6.4, 2.8 Hz), 6.63-6.56 (m,1H), 4.20 (t, 2H, J=6.4 Hz), 3.22 and 3.10 (d of ABq, 2H, J=13.8 Hz),3.04 (t, 2H, J=6.4 Hz), 2.41 (s, 3H), 1.38 (s, 3H).

Example 572-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method ofExample 56. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, d, 1H, J=3.6 Hz), 7.39(d, 1H, J=5.2 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.08 (dd, 1H, J=5.2, 3.6 Hz),7.00 (q, 1H, J=9.5 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.78 (ddd, 1H, J=11.6,6.4, 2.8 Hz), 6.65-6.60 (m, 1H), 4.18 (t, 2H, J=6.4 Hz), 3.22 and 3.12(d of ABq, 2H, J=13.6 Hz), 2.98 (t, 2H, J=6.4 Hz), 2.37 (s, 3H), 1.40(s, 3H).

Example 583-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionicacid

The title compound was prepared from2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester using the method ofExample 56. ¹H NMR (400 MHz, CDCl₃) δ 9.37 (bs, 1H), 7.16 (d, 2H, J=8.4Hz), 6.99 (dd, 1H, J=9.5 Hz), 6.78 (d, 2H, J=8.4 Hz), 6.77-6.72 (m, 1H),6.63-6.58 (m, 1H), 4.12 (t, 2H, J=6.4 Hz), 3.21 and 3.08 (d of ABq, 2H,J=14.0 Hz), 2.97 (t, 2H, J=6.4 Hz), 2.91 (tt, 1H, J=12.0, 3.6 Hz), 2.32(s, 3H), 2.04-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.76-1.68 (m, 1H),1.62-1.49 (m, 2H), 1.41-1.19 (m, 3H), 1.37 (s, 3H).

Example 592-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using themethod of Example 56. ¹H NMR (400 MHz, CDCl₃) δ 7.15 (d, 2H, J=8.60 Hz),7.00 (q, 1H, J=8.99 Hz), 6.79 (d, 2H, J=8.60 Hz), 6.77-6.74 (m, 1H),6.63-6.61 (m, 1H), 4.12 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz),3.09 (d, 1H, J=14.08 Hz), 2.97 (t, 2H, J=6.25 Hz), 2.31 (s, 3H),2.16-2.08 (m, 2H), 1.61-1.35 (m, 8H), 1.39 (s, 3H), 1.29 (s, 3H); MS(ES⁺) calcd for C₂₉H₃₄NO₅F₂: Found m/e 514.3 (M+1, 100%).

Example 602-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-m-tolyloxy-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl esterand toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethylester using Standard Procedure (B). ¹H NMR (400 MHz, CDCl₃) δ 8.04-8.01(m, 2H), 7.47-7.45 (m, 3H), 7.18 (d, 2H, J=8.60 Hz), 7.13 (t, 1H, J=7.82Hz), 6.87-6.85 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.74-6.67 (m, 2H), 4.23(t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.12 (d, 1H, J=13.69 Hz),3.06 (t, 2H, J=6.26 Hz), 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₂₉H₃₀NO₅ 472.2124, found 472.2098.

Example 612-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-m-tolyloxy-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester andtoluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethylester using the procedure of Example 60. ¹H NMR (400 MHz, CDCl₃) δ 7.76(d, 1H, J=3.52 Hz), 7.46 (d, 1H, J=4.69 Hz), 7.17 (d, 2H, J=8.21 Hz),7.16-7.10 (m, 2H), 6.87-6.86 (m, 1H), 6.81 (d, 2H, J=8.60 Hz), 6.72-6.69(m, 2H), 4.21 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.12 (d, 1H,J=14.08 Hz), 3.01 (t, 2H, J=6.26 Hz), 2.38 (s, 3H), 2.30 (s, 3H), 1.41(s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₇H₂₈NO₅S 478.1688, found478.1692.

Example 623-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionicacid

The title compound was prepared from3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester andtoluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl esterusing the procedure of Example 60. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d,2H, J=8.60 Hz), 7.13 (t, 1H, J=7.82 Hz), 6.85 (d, 1H, J=7.43 Hz), 6.78(d, 2H, J=8.60 Hz), 6.69-6.68 (m, 2H), 4.16 (t, 2H, J=5.86 Hz), 3.20 (d,1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08 Hz), 3.09-2.96 (m, 3H), 2.33 (s,3H), 2.30 (s, 3H), 2.06-2.02 (m, 2H), 1.83-1.80 (m, 2H), 1.73-1.70 (m,1H), 1.59-1.56 (m, 2H), 1.41 (s, 3H), 1.38-1.26 (m, 3H); HRMS (ES⁺) m/zexact mass calcd for C₂₉H₃₆NO₅ 478.2593, found 478.2592.

Example 632-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ8.00-7.97 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.99 Hz), 6.93-6.82(m, 6H), 4.21 (t, 2H, J=6.65 Hz), 3.21 (d, 1H, J=14.08 Hz), 3.13 (d, 1H,J=14.08 Hz), 3.01 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 1.36 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₂₈H₂₇NO₅F 476.1873, found 476.1871.

Example 642-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedureof Example 63. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, 1H, J=3.52 Hz, J=1.17Hz), 7.36 (dd, 1H, J=5.08 Hz, J=1.17 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.06(dd, 1H, J=5.08 Hz, J=3.91 Hz), 6.93-6.85 (m, 4H), 6.82 (d, 2H, J=8.60Hz), 4.18 (t, 2H, J=6.65 Hz), 3.21 (d, 1H, J=13.69 Hz), 3.13 (d, 1H,J=13.69 Hz), 2.96 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.36 (s, 3H); HRMS(ES⁺) m/z exact mass calcd for C₂₆H₂₅NO₅FS 482.1437, found 482.1451.

Example 653-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

The title compound was prepared from2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure ofExample 63. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, 2H, J=8.60 Hz), 6.95-6.85(m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.20 (d, 1H,J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.85(tt, 1H, J=11.73 Hz, J=3.52 Hz), 2.30 (s, 3H), 2.02-1.99 (m, 2H),1.83-1.78 (m, 2H), 1.72-1.69 (m, 1H), 1.58-1.49 (m, 2H), 1.36 (s, 3H),1.33-1.22 (m, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₈H₃₃NO₅F482.2343, found 482.2347.

Example 662-(4-Fluoro-phenoxy)-2-methyl-3-(4-[2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy]-phenyl)-propionicacid

The title compound was prepared from2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using theprocedure of Example 63. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, 2H, J=8.60Hz), 6.93-6.84 (m, 4H), 6.69 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.06Hz), 3.22 (d, 1H, J=13.68 Hz), 3.09 (d, 1H, J=13.06 Hz), 2.98 (t, 2H,J=6.06 Hz), 2.31 (s, 3H), 2.17-2.09 (m, 2H), 1.57-1.50 (m, 4H),1.45-1.37 (m, 4H), 1.35 (s, 3H), 1.31 (s, 3H); MS (ES⁺) calcd forC₂₉H₃₅NO₅F: Found m/e 496.3 (M+1, 100%).

Example 67(S)-2-(4-Fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(S)-2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester and toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester (95% ee;Chiralpak AD separation, 8×28 cm, 10% IPA/heptane, 275 nm) by theprocedure described in Example 1.

Example 68(S)-2-(4-Methanesulfonyl-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from3-(4-hydroxyphenyl)-2-(4-methanesulfonyl-phenoxy)-2-methyl-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ8.00 (d, 2H, J=7.04 Hz), 7.80 (d, 2H, J=9.00 Hz), 7.55-7.50 (m, 3H),7.14 (d, 2H, J=8.60 Hz), 6.97 (d, 2H, J=9.00 Hz), 6.80 (d, 2H, J=8.21Hz), 4.20 (t, 2H, J=5.87 Hz), 3.29 (d, 1H, J=14.08 Hz), 3.17 (d, 1H,J=14.08 Hz), 3.10 (t, 2H, J=5.87 Hz), 3.01 (s, 3H), 2.46 (s, 3H), 1.54(s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₀NO₇S 536.1743, found536.1771.

Example 692-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-nitro-phenoxy)-propionicacid

Standard Procedure (B) was utilized to prepare the title compound fromtoluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, 2H, J=9.00 Hz), 8.05-7.96 (m, 2H),7.52-7.45 (m, 3H), 7.14 (d, 2H, J=8.60 Hz), 6.90 (d, 2H, J=9.00 Hz),6.80 (d, 2H, J=8.60 Hz), 4.20 (t, 2H, J=5.87 Hz), 3.29 (d, 1H, J=14.08Hz), 3.18 (d, 1H, J=14.08 Hz), 3.08 (t, 2H, J=5.87 Hz), 2.45 (s, 3H),1.55 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₈H₂₇N₂O₇ 503.1818,found 503.1850.

Example 702-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-trifluoromethyl-phenoxy)-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from3-(4-hydroxy-phenyl)-2-methyl-2-(3-trifluoromethyl-phenoxy)-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ7.99-7.97 (m, 2H), 7.50-7.46 (m, 3H), 7.33 (t, 1H, J=8.21 Hz), 7.26-7.24(m, 1H), 7.17 (d, 2H, J=8.60 Hz), 7.14-7.12 (m, 1H), 7.04-7.01 (m, 1H),6.81 (d, 2H, J=8.60 Hz), 4.20 (t, 2H, J=5.87 Hz), 3.27 (d, 1H, J=14.08Hz), 3.14 (d, 1H, J=14.08 Hz), 3.07 (t, 2H, J=5.87 Hz), 2.42 (s, 3H),1.44 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₂₇NO₅F₃ 526.1841,found 526.1845.

Example 712-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-methyl-2-(3-trifluoromethyl-phenoxy)-propionicacid ethyl ester using the procedure of Example 70.

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, 1H, J=3.51 Hz), 7.47 (d, 1H, J=5.08Hz), 7.35 (t, 1H, J=8.01 Hz), 7.29-7.27 (m, 1H), 7.19-7.11 (m, 4H),7.08-7.03 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 4.18 (t, 2H, J=6.26 Hz),3.27 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 3.02 (t, 2H, J=6.26Hz), 2.39 (s, 3H), 1.46 (s, 3H); HRMS (ES⁺) m/z exact mass calcd forC₂₇H₂₅NO₅F₃S 532.1405, found 532.1423.

Example 723-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-trifluoromethyl-phenoxy)-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-methyl-2-(3-trifluoromethyl-phenoxy)-propionicacid ethyl ester using the procedure of Example 70.

¹H NMR (400 MHz, CDCl₃) δ 7.35 (t, 1H, J=7.82 Hz), 7.28-7.26 (m, 1H),7.16 (d, 2H, J=8.60 Hz), 7.13-7.12 (m, 1H), 7.05-7.02 (m, 1H), 6.78 (d,2H, J=8.60 Hz), 4.14 (t, 2H, J=5.67 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.13(d, 1H, J=14.08 Hz), 3.01-2.93 (m, 3H), 2.35 (s, 3H), 2.05-2.01 (m, 2H),1.83-1.78 (m, 2H), 1.73-1.69 (m, 1H), 1.58-1.49 (m, 2H), 1.45 (s, 3H),1.37-1.18 (m, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₃NO₅F₃532.2311, found 532.2305.

Example 732-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionicacid

Standard Procedure (B) was utilized to prepare the title compound fromtoluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)ethyl ester. ¹H NMR (400MHz, CDCl₃) δ 7.34 (t, 1H, J=8.01 Hz), 7.28-7.26 (m, 1H), 7.16 (d, 2H,J=8.60 Hz), 7.13-7.13 (m, 1H), 7.06-7.01 (m, 1H), 6.79 (d, 2H, J=8.60Hz), 4.14 (t, 2H, J=6.25 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.13 (d, 1H,J=14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.34 (s, 3H), 2.14-2.08 (m, 2H),1.62-1.32 (m, 8H), 1.45 (s, 3H), 1.31 (s, 3H); MS (ES⁺) calcd forC₃₀H₃₅NO₅F₃: Found m/e 546.2 (M+1, 100%).

Example 742-(3-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ7.97-7.95 (m, 2H), 7.42-7.39 (m, 3H), 7.18-7.12 (m, 3H), 6.83 (d, 2H,J=8.99 Hz), 6.61-6.58 (m, 1H), 6.52-6.46 (m, 2H), 4.21 (t, 2H, J=6.65Hz), 3.74 (s, 3H), 3.25 (d, 1H, J=13.69 Hz), 3.15 (d, 1H, J=13.69 Hz),2.98 (t, 2H, J=6.65 Hz), 2.37 (s, 3H), 1.45 (s, 3H); HRMS (ES⁺) m/zexact mass calcd for C₂₉H₃₀NO₆ 488.2073, found 488.2083.

Example 752-(3-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedureof Example 74. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, 1H, J=3.52 Hz), 7.36(d, 1H, J=5.08 Hz), 7.17-7.13 (m, 3H), 7.08-6.99 (m, 1H), 6.82 (d, 2H,J=8.60 Hz), 6.62-6.59 (m, 1H), 6.52-6.46 (m, 2H), 4.19 (t, 2H, J=6.65Hz), 3.75 (s, 3H), 3.24 (d, 1H, J=14.08 Hz), 3.16 (d, 1H, J=14.08 Hz),2.95 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.45 (s, 3H); HRMS (ES⁺) m/zexact mass calcd for C₂₇H₂₈NO₆S 494.1637, found 494.1642.

Example 763-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-methoxy-phenoxy)-2-methyl-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester using the procedure ofExample 74. ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.12 (m, 3H), 6.77 (d, 2H,J=8.99 Hz), 6.61-6.59 (m, 1H), 6.50-6.47 (m, 1H), 6.46 (t, 1H, J=2.35Hz), 4.14 (t, 2H, J=6.06 Hz), 3.75 (s, 3H), 3.25 (d, 1H, J=14.08 Hz),3.13 (d, 1H, J=14.08 Hz), 3.00-2.94 (m, 3H), 2.33 (s, 3H), 2.05-2.01 (m,2H), 1.83-1.80 (m, 2H), 1.75-1.69 (m, 1H), 1.58-1.54 (m, 2H), 1.44 (s,3H), 1.37-1.26 (m, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₆NO₆494.2543, found 494.2543.

Example 772-(3-Methoxy-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using theprocedure of Example 74. ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.13 (m, 3H),6.79 (d, 2H, J=8.60 Hz), 6.61-6.59 (m, 1H), 6.51-6.48 (m, 1H), 6.46 (t,1H, J=2.35 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.75 (s, 3H), 3.24 (d, 1H,J=13.68 Hz), 3.12 (d, 1H, J=13.68 Hz), 2.96 (t, 2H, J=6.25 Hz), 2.30 (s,3H), 2.15-2.08 (m, 2H), 1.61-1.45 (m, 5H), 1.44 (s, 3H), 1.43-1.36 (m,3H), 1.30 (s, 3H); MS (ES⁺) calcd for C₃₀H₃₈NO₆: Found m/e 508.3 (M+1,100%).

Example 782-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

Standard Procedure (B) was utilized to prepare the title compound from2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ7.96-7.93 (m, 2H), 7.44-7.41 (m, 3H), 7.13 (d, 2H, J=8.79 Hz), 6.78 (d,2H, J=8.79 Hz), 6.60 (d, 1H, J=8.79 Hz), 6.41 (d, 1H, J=2.44 Hz), 6.32(dd, 1H, J=8.79 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.17 (t, 2H,J=6.35 Hz), 3.15 (d, 1H, J=14.16 Hz), 3.04-3.00 (m, 3H), 2.38 (s, 3H),1.30 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₉H₂₈NO₇ 502.1866,found 502.1881.

Example 792-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl propionicacid ethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedureof Example 78. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, 1H, J=3.90 Hz, J=1.47Hz), 7.35 (dd, 1H, J=5.37 Hz, J=1.47 Hz), 7.13 (d, 2H, J=8.31 Hz), 7.04(dd, 1H, J=5.37 Hz, J=3.90 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H,J=8.30 Hz), 6.42 (d, 1H, J=2.44 Hz), 6.33 (dd, 1H, J=8.31 Hz, J=2.44Hz), 5.88 (d, 2H, J=0.98 Hz), 4.15 (t, 2H, J=6.35 Hz), 3.16 (d, 1H,J=13.92 Hz), 3.04 (d, 1H, J=13.92 Hz), 2.93 (t, 2H, J=6.35 Hz), 2.31 (s,3H), 1.30 (s, 3H); HRMS (ES⁺) m/z exact mass calcd for C₂₇H₂₆NO₇S508.1430, found 508.1425.

Example 802-(Benzo[1,3]dioxol-5-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

The title compound was prepared from2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure ofExample 78. ¹H NMR (400 MHz, CDCl₃) δ 7.13 (d, 2H, J=8.30 Hz), 6.75 (d,2H, J=8.79 Hz), 6.61 (d, 2H, J=8.30 Hz), 6.42 (d, 2H, J=2.44 Hz), 6.33(dd, 1H, J=8.30, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.11 (t, 2H,J=5.86 Hz), 3.15 (d, 1H, J=13.68 Hz), 3.03 (d, 1H, J=13.68 Hz), 2.93 (t,2H, J=5.86 Hz), 2.86 (tt, 1H, J=11.72 Hz, J=3.42 Hz), 2.27 (s, 3H),1.99-1.96 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H), 1.57-1.46 (m,2H), 1.37-1.33 (m, 1H), 1.32 (s, 3H), 1.29-1.19 (m, 2H); HRMS (ES⁺) m/zexact mass calcd for C₂₉H₃₄NO₇ 508.2335, found 508.2351.

Example 812-(Benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionicacid ethyl ester and toluene-4-sulfonic acid2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]-ethyl ester using theprocedure of Example 78. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, 2H, J=8.60Hz), 6.79 (d, 2H, J=8.60 Hz), 6.65 (d, 1H, J=8.21 Hz), 6.47 (d, 1H,J=2.35 Hz), 6.37 (dd, 1H, J=8.21 Hz, J=2.35 Hz), 5.92 (d, 2H, J=0.78Hz), 4.14 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz), 3.07 (d, 1H,J=14.08 Hz), 2.98 (t, 2H, J=6.25 Hz), 2.31 (s, 3H), 2.17-2.08 (m, 2H),1.62-1.35 (m, 8H), 1.34 (s, 3H), 1.31 (s, 3H); MS (ES⁺) calcd forC₃₀H₃₅NO₇: Found m/e 522.3 (M+1, 100%).

Example 822-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

Standard Procedure (B) was utilized to prepare the title compound from2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester andtoluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.¹H NMR (400 MHz, CDCl₃) δ 7.97-7.94 (m, 2H), 7.42-7.40 (m, 3H),7.31-7.27 (m, 2H), 7.06 (t, 1H, J=7.43 Hz), 6.98 (t, 4H, J=8.99 Hz),6.75 (d, 2H, J=8.60 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.29 (s, 2H), 2.96 (t,2H, J=6.65 Hz), 2.36 (s, 3H), 2.10-1.98 (m, 2H), 1.42-1.16 (m, 4H), 0.79(t, 3H, J=7.04 Hz); MS (ES⁺) calcd for C₃₁H₃₄NO₅: Found m/e 500.2 (M+1,100%).

Example 832-{4-[2-(5-Methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester and whatfollowing the procedure of Example 84. ¹H NMR (400 MHz, CDCl₃) δ 7.49(dd, 1H, J=3.91 Hz, J=1.17 Hz), 7.28 (dd, 1H, J=5.08 Hz, J=1.17 Hz),7.21 (dd, 2H, J=8.60 Hz, J=7.43), 6.99-6.95 (m, 2H), 6.92-6.87 (m, 4H),6.66 (d, 2H, J=8.60 Hz), 4.07 (t, 2H, J=6.65 Hz), 3.21 (s, 2H), 2.85 (t,2H, J=6.65 Hz), 2.26 (s, 3H), 2.02-1.88 (m, 2H), 1.32-1.09 (m, 4H), 0.71(t, 3H, J=7.04 Hz); MS (ES⁺) calcd for C₂₉H₃₂NO₅S: Found m/e 506.2 (M+1,100%).

Example 842-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoicacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester and whatfollowing the procedure of Example 82. ¹H NMR (400 MHz, CDCl₃) δ 7.29(dd, 2H, J=8.60 Hz, J=7.43 Hz), 7.06-6.94 (m, 5H), 6.70 (d, 2H, J=8.60Hz), 4.09 (t, 2H, J=5.86 Hz), 3.30 (d, 1H, J=14.65 Hz), 3.27 (d, 1H,J=14.65 Hz), 2.95-2.86 (m, 3H), 2.30 (s, 3H), 2.08-1.92 (m, 4H),1.83-1.79 (m, 2H), 1.72-1.69 (m, 1H), 1.60-1.50 (m, 2H), 1.42-1.18 (m,7H), 0.71 (t, 3H, J=7.04 Hz); MS (ES⁺) calcd for C₃₁H₄₀NO₅: Found m/e506.3 (M+1, 100%).

Example 852-(4-{2-[5-Methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoicacid

The title compound was prepared from2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester and whatfollowing the procedure of Example 82. ¹H NMR (400 MHz, CDCl₃) δ 7.29(t, 2H, J=8.01 Hz), 7.06 (t, 1H, J=7.43 Hz), 7.00-6.95 (m, 4H), 6.71 (d,2H, J=8.60 Hz), 4.10 (t, 2H, J=5.86 Hz), 3.28 (s, 2H), 2.96 (t, 2H,J=5.86 Hz), 2.30 (s, 3H), 2.13-1.95 (m, 4H), 1.62-1.15 (m, 12H), 1.31(s, 3H), 0.79 (t, 3H, J=7.04 Hz); MS (ES⁺) calcd for C₃₂H₄₂NO₅: Foundm/e 520.3 (M+1, 100%).

Example 86(S)-2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

Step A 2-(3-Phenyl-propionylamino)-succinic acid 4-methyl ester

Methyl L-aspartate (15.0 g, 0.082 mol), DI water (245 mL), acetone (20mL), and Na₂CO₃ (30.8 g, 0.286 mol) were combined and cooled thesolution to 5° C. 3-Phenyl-propionyl chloride (13.3 mL, 0.089 mol) wasadded dropwise via addition funnel over 10 min. The reaction was allowedto warm to ambient temperature and stir for 2 h. The reaction becamevery thick during this time. Added conc. HCl (50 mL) to the slurry untilthe pH was ≦4.0. The reaction mixture was extracted with CH₂Cl₂ (3×).The organic phase was washed with water and then dried (MgSO₄), filteredand concentrated under reduced pressure. The clear, colorless oil wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (br s,1H), 7.28-7.17 (m, 5H), 6.57 (d, J=7.6 Hz, 1H), 4.87 (m, 1H), 3.67 (s,3H), 2.96 (t, J=7.6 Hz, 2H), 2.89 (A of ABX, J_(AB)=17.6 Hz, J_(AX)=4.8Hz, 1H), 2.88 (B of ABX, J_(BA)=17.6 Hz, J_(BX)=4.0 Hz, 1H), 2.69 (t,J=7.6 Hz, 2H); MS (EI+) 280 (M+H), 302 (M+H+Na).

Step B 4-Oxo-3-(3-phenyl-propionylamino)-pentanoic acid methyl ester

2-(3-Phenyl-propionylamino)-succinic acid 4-methyl ester (10 g, 36mmol), pyridine (50 mL) and acetic anhydride (45 mL) were combined in a500 mL flask. The reaction mixture was heated at 90° C. for 2 h and thencooled to ambient temperature. After concentrating the reaction mixtureunder reduced pressure, DI water was added (100 mL). (Potentialexotherm!). The reaction mixture was partitioned between water andCH₂Cl₂. The organic phase was washed with 1N HCl and then dried (MgSO₄),filtered and concentrated under reduced pressure. The material was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.20 (m,5H), 6.79 (br d, J=7.6 Hz, 1H), 4.72 (X of ABX, 1H), 3.65 (s, 3H),3.01-2.93 (m, 3H), 2.71-2.62 (m, 3H), 2.11 (s, 3H); MS (EI) 278.1 (M+H).

Step C (5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid methyl ester

In a 100 mL flask, 4-oxo-3-(3-phenyl-propionylamino)-pentanoic acidmethyl ester (10 g, 36 mmol), and acetic anhydride (28 mL) werecombined. Following addition of concentrated H₂SO₄ (1 mL), the solutionwas heated to 90° C. for 30 min and then cooled to ambient temperature.The reaction was slowly diluted with DI water (30 mL, potentialexotherm). The reaction mixture was partitioned between CH₂Cl₂ andwater. The organic phase was washed with DI water, 10% NaHCO₃ (aq),brine (150 mL), and then dried over MgSO₄ and concentrated to obtain abrown oil. The residue was purified by column chromatography (600 mLSiO₂, 35% EtOAc/hexanes) to provide the desired product (3.25 g) as apale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.20 (m, 5H), 3.72 (s,3H), 3.47 (s, 2H), 3.08-2.96 (m, 4H), 2.24 (s, 3H); MS (EI+) 260 (M+H).

Step D (5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid

(5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid methyl ester (8.75 g,33.8 mmol), in MeOH (120 mL) was treated with 5N NaOH (40 mL) and thenthe solution was warmed to 40° C. After 40 min, the reaction mixture wasconcentrated under reduced pressure, suspended in water, and thenacidified to pH=1 with 5N HCl. The mixture was extracted with EtOAc(2×), dried (MgSO₄), and concentrated to provide 5.25 g (63%) of theproduct as an off-white solid. ¹H NMR (400 MHz, CDCl₃) •• ¹H NMR (400MHz, CDCl₃) δ 7.33-7.20 (m, 5H), 3.52 (s, 2H), 3.06-3.03 (m, 4H), 2.24(s, 3H).

Step E 2-(5-Methyl-2-phenethyl-oxazol-4-yl)-ethanol

BH₃-THF complex (49 mL of a 1.0 M solution in THF) was added dropwisevia addition funnel over 50 min to a solution of(5-methyl-2-phenethyl-oxazol-4-yl)-acetic acid (5.05 g, 20.6 mmol) inTHF (35 mL). The reaction mixture was stirred at ambient temperature for3 h, and then quenched with MeOH (12 mL). After heating at 50° c for 2h, the reaction mixture was cooled to ambient temperature, and thenpartitioned between CH₂Cl₂ and 1N NaOH. The organic phase was washedwith brine (1×50 mL), dried over MgSO₄ and concentrated to obtain aresidue which was purified by column chromatography (500 mL SiO₂, 35%EtOAc/hexanes) to provide 3.99 g (84%) of the desired product as aclear, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.20 (m, 5H), 3.84(q, J=5.6 Hz, 2H), 3.06-2.67 (m, 4H), 2.62 (t, J=5.6 Hz, 2H), 2.22 (s,3H); MS (EI+) 232.19 (M+H); 254.15 (M+H+Na).

Step F Toluene-4-sulfonic acid2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethyl ester

A solution of 2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethanol (1.2 g, 5.19mmol) in CH₂Cl₂ at 0° C. was treated with pyridine (1.64 g, 20.7 mmol,1.68 mL), DMAP (190 mg, 1.56 mmol), and tosyl anhyride (2.2 g, 6.75mmol). The reaction was warmed to ambient temperature and, after 90 min,the solution was filtered through a pad of silica gel (rinsed withCH₂Cl₂). The product was used without further purification. ¹H NMR (400MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.31-7.17 (m, 7H), 4.21 (t, J=6.8Hz, 2H), 3.01-2.88 (m, 4H), 2.75 (t, J=6.8 Hz, 2H), 2.43 (s, 3H), 2.19(s, 3H).

Step G(S)-2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester

(S)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(298 mg, 1.0 mmol), toluene-4-sulfonic acid2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethyl ester (460 mg, 1.19 mmol) andCs₂CO₃ (388 mg, 1.19 mmol) are combined in anhydrous DMF (8 mL) andstirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixturewas then cooled and diluted with ethyl acetate (50 mL), and washed withwater then brine. The organic layer was dried with MgSO₄ andconcentrated in vacuo to a viscous tan oil. The residue was purified byflash column chromatography (200 g silica, hexanes to 25% EtOAc/hexanes)to provide unreacted phenol (80 mg) and the title compound as acolorless oil (340 mg, 67% (91% based on recovered phenol)). ¹H NMR (400MHz, CDCl₃) δ 7.31-7.17 (m, 9H), 6.98 (tt, J=7.2, 1.2 Hz, 1H), 6.87-6.83(m, 4H), 4.22 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H), 3.29 (A of Abq,J=14.0 Hz, 1H), 3.13 (B of Abq, J=14.0 Hz, 1H), 3.01-2.97 (m, 4H), 2.89(t, J=6.8 Hz, 2H), 2.26 (s, 3H), 1.42 (s, 3H), 1.23 (t, J=7.2 Hz, 3H);MS (EI+) 514.27 (M+H).

Step H(S)-2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

(S)-2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (340 mg, 0.66 mmol) in MeOH (10 mL) was treated with 2NNaOH (10 mL) and warmed to 55° C. After 18 h, the mixture wasconcentrated under reduced pressure and then acidified with 5N HCl topH=1. The solution was extracted with EtOAc and then the organic phasesdried (MgSO₄), filtered and concentrated to a white foam (273 mg, 85%):¹H NMR (400 MHz, CDCl₃) δ 9.00 (br s, 1H), 7.27-7.15 (m, 9H), 6.95 (t,J=7.3 Hz, 1H), 6.91 (d, J=7.7 Hz, 2H), 6.78 (d, J=7.7 Hz, 2H), 4.10 (t,J=6.2 Hz, 2H), 3.27 (A of ABq, J=13.9 Hz, 1H), 3.13 (B of ABq, J=13.9Hz, 1H), 3.04 (s, 4H), 2.89 (t, J=6.2 Hz, 2H), 2.26 (s, 3H), 1.41 (s,3H); MS (EI+) 486.1 (M+H), (EI−) 484.1 (M−H).

Example 872-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

Step A2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester

Racemic 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl esterwas coupled by the procedure of Example 88, Step G, to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.19 (m, 7H), 7.15 (d, J=8.4Hz, 2H), 6.97 (t, J=7.2, 1H), 6.84-6.81 (m, 4H), 4.21 (q, J=7.2 Hz, 2H),4.16 (t, J=6.8 Hz, 2H), 3.27 (A of Abq, J=14.0 Hz, 1H), 3.11 (B of Abq,J=14.0 Hz, 1H), 3.07-2.95 (m, 4H), 2.88 (t, J=6.8 Hz, 2H), 2.26 (s, 3H),1.40 (s, 3H), 1.22 (t, J=7.2 Hz, 3H).

Step B2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid

The title compound was mage according to the procedure of Example 88,Step H. ¹H NMR (400 MHz, CDCl₃) δ 9.15 (br s, 1H), 7.27-7.08 (m, 9H),6.89 (t, J=7.3 Hz, 1H), 6.82 (d, J=7.7 Hz, 2H), 6.74 (d, J=7.7 Hz, 2H),4.07 (t, J=6.2 Hz, 2H), 3.19 (A of ABq, J=13.9 Hz, 1H), 3.03 (B of ABq,J=13.9 Hz, 1H), 3.04-2.96 (m, 4H), 2.84 (t, J=6.2 Hz, 2H), 2.23 (s, 3H),1.27 (s, 3H).

Example 88(S)-2-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid

Step A 2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methylester

A mixture of 5-methyl-2-thiophenecarboxylic acid (6.44 g, 45.4 mmol),N-methyl-morpholine (4.82 g, 47.7 mmol), and2-chloro-4,6-dimethyl-1,3,5-triazine (8.2 g, 46.7 mmol) in THF (100 mL)was stirred at ambient temperature for 90 min. β-Methyl L-aspartate (8.6g, 46.7 mmol), N-methylmorpholine (9.64 g, 95.3 mmol), and distilledwater (10 mL) were added and the mixture was stirred 3 h. The reactionwas partitioned between CH₂Cl₂ and 1N HCl. The organic phase was dried(MgSO₄), filtered and concentrated under reduced pressure. The clear,colorless oil was used without further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.39 (d, J=3.6 Hz, 1H), 7.09 (br d, J=7.6 Hz, 1H), 6.74 (dd,J=3.6, 0.8 Hz, 1H), 5.00 (m, 1H), 4.07 (s, 3H), 3.06 (A of ABX,J_(AB)=17.6 Hz, J_(AX)=4.4 Hz, 1H), 3.05 (B of ABX, J_(BA)=17.6 Hz,J_(BX)=4.8 Hz, 1H), 2.51 (s, 3H).

Step B 3-[(5-Methyl-thiophene-2-carbonyl)-amino]-4-oxo-pentanoic acidmethyl ester

2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methyl ester(12 g, 45 mmol), pyridine (60 mL) and acetic anhydride (50 mL) werecombined in a 500 mL flask. The reaction mixture was heated at 90° C.for 2 h and then cooled to ambient temperature. After concentrating thereaction mixture under reduced pressure, DI water was added (100 mL).(Potential exotherm!). The reaction mixture was partitioned betweenwater and CH₂Cl₂. The organic phase was washed with 1N HCl and thendried (MgSO₄), filtered and concentrated under reduced pressure. Thematerial was used without further purification. MS (EI) 270.1 (M+H).

Step C [5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acidmethyl ester

In a 100 mL flask,3-[(5-methyl-thiophene-2-carbonyl)-amino]-4-oxo-pentanoic acid methylester (12 g, 45 mmol), and acetic anhydride (30 mL) were combined.Following addition of concentrated H₂SO₄ (1 mL), the solution was heatedto 90° C. for 30 min and then cooled to ambient temperature. Thereaction was slowly diluted with DI water (30 mL, potential exotherm).The reaction mixture was partitioned between CH₂Cl₂ and water. Theorganic phase was washed with DI water and brine (150 mL), and thendried over MgSO₄ and concentrated to obtain a brown oil. The residue waspurified by column chromatography (700 mL SiO₂, 30% EtOAc/hexanes) toprovide the desired product (3.44 g) as a pale yellow oil. R_(f)=0.39(50% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=3.6 Hz, 1H),6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 2.51 (s, 3H),2.32 (s, 3H).

Step D [5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acid

[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acid methylester (3.44 g, 13.7 mmol), in MeOH (45 mL) was treated with 5N NaOH (16mL) and then the solution was warmed to 40° C. After 30 min, thereaction mixture was concentrated under reduced pressure, suspended inwater, and then acidified to pH=1 with 5N HCl. The mixture was extractedwith EtOAc (2×), dried (MgSO₄), and concentrated to provide 2.47 g (76%)of the product as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d,J=3.6 Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.59 (s, 2H), 2.51 (s, 3H),2.32 (s, 3H).

Step E 2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethanol

BH₃-THF complex (15 mL of a 1.0 M solution in THF) was added dropwisevia addition funnel over 50 min to a solution of[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acid (1.5 g,6.33 mmol) in THF (10 mL). The reaction mixture was stirred at ambienttemperature for 3 h, and then quenched with MeOH (4 mL). After heatingat 50° C. for 2 h, the reaction mixture was cooled to ambienttemperature, and then partitioned between CH₂Cl₂ and 1N NaOH. Theorganic phase was washed with brine (1×50 mL), dried over MgSO₄ andconcentrated to obtain a colorless oil (1.4 g, 99%) which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J=3.6Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.89 (q, J=5.6 Hz, 2H), 3.04 (t,J=5.9 Hz, 1H), 2.68 (t, J=5.6 Hz, 2H), 2.51 (s, 3H), 2.30 (s, 3H); MS(EI+) 224.04 (M+H); 246.06 (M+H+Na).

Step F Toluene-4-sulfonic acid2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethyl ester

A solution of2-(5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethanol (1.42 g,6.37 mmol) in CH₂Cl₂ (25 mL) at 0° C. was treated with pyridine (2.0 g,25.5 mmol, 2.0 mL), DMAP (233 mg, 1.91 mmol), and tosyl anhyride (2.70g, 8.28 mmol). The reaction was warmed to ambient temperature and, after90 min, the solution was filtered through a pad of silica gel (rinsedwith CH₂Cl₂). The product was used without further purification. MS(EI+) 378.1 (M+H).

Step G(S)-2-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid ethyl ester

(S)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(255 mg, 0.85 mmol), toluene-4-sulfonic acid2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]ethyl ester (383 mg,1.02 mmol) and Cs₂CO₃ (335 mg, 1.02 mmol) are combined in anhydrous DMF(6 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen.The mixture was then cooled and diluted with ethyl acetate (50 mL), andwashed with water then brine. The organic layer was dried with MgSO₄ andconcentrated in vacuo to a viscous tan oil. The residue was purified byflash column chromatography (200 g silica, hexanes to 25% EtOAc/hexanes)to provide the title compound as a colorless oil (201 mg, 47%). ¹H NMR(400 MHz, CDCl₃) δ 7.39 (d, J=3.4 Hz, 1H), 7.22-7.13 (m, 4H), 6.97 (t,J=7.2 Hz, 1H), 6.85-6.80 (m, 4H), 6.72 (dd, J=3.6, 1.2 Hz, 1H),4.23-4.17 (m, 4H), 3.26 (A of Abq, J=13.6 Hz, 1H), 3.11 (B of Abq,J=13.6 Hz, 1H), 2.94 (t, J=5.6 Hz, 2H), 2.50 (s, 3H), 2.34 (s, 3H), 1.39(s, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (EI+) 505.9 (M+H); 637.8 (M+H+Cs).

Step H(S)-2-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid

(S)-2-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyricacid ethyl ester (201 mg, 0.40 mmol) in MeOH (8 mL) was treated with 2NNaOH (8 mL) and warmed to 55° C. After 18 h, the mixture wasconcentrated under reduced pressure and then acidified with 5N HCl topH=1. The solution was extracted with EtOAc and then the organic phasesdried (MgSO₄), filtered and concentrated to a white foam (158 mg, 81%)that was dried in a vacuum oven at 50° C. for 24 h: ¹H NMR (400 MHz,CDCl₃) δ 7.36 (d, J=3.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 2H), 7.10 (d, J=8.4Hz, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.83 (d, J=7.6 Hz, 2H), 6.75 (d, J=8.8Hz, 2H), 6.71 (dd, J=3.6, 0.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.18 (Aof Abq, J=13.6 Hz, 1H), 3.00 (B of Abq, J=13.6 Hz, 1H), 2.90 (t, J=6.8Hz, 2H), 2.49 (s, 3H), 2.31 (s, 3H), 1.31 (s, 3H).

Example 892-(4-{2-[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxybutyric acid

The title compound was prepared in the manner of Example 86 from racemic3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester andtoluene-4-sulfonic acid2-[5-methyl-2-5-methyl-thiophen-2-yl)-oxazol-4-yl)-ethyl ester. ¹H NMR(400 MHz, CDCl₃) δ 7.35 (d, J=3.2 Hz, 1H), 7.03-6.99 (m, 4H), 6.83 (t,J=7.2 Hz, 1H), 6.75-6.70 (m, 5H), 4.08 (t, J=6.4 Hz, 2H), 3.12 (A ofAbq, J=13.6 Hz, 1H), 2.86 (t, J=6.4 Hz, 2H), 2.81 (B of Abq, J=13.6 Hz,1H), 2.48 (s, 3H), 2.27 (s, 3H), 1.12 (s, 3H).

Example 902-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionicacid

Step A 3-Hydroxy-2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid

To a 2.0 M solution of LDA in THF/heptane/ethyl benzene (200 mL, 408mmol) cooled by an ice/acetone bath, a 0.75 M solution of2-phenoxypropionic acid (30.8 g, 185 mmol) in THF (250 mL) was addeddropwise over 30 min, keeping the reaction temperature below −10° C.After allowing the reaction mixture to stir for 15 min, a 0.75 Msolution of 2-thiophenecarboxaldehyde (20.8 g, 185 mmol) in THF (250 mL)was added dropwise over the course of 1 h, maintaining the reactiontemperature below −5° C. After stirring for 5 min at 0° C., HPLCanalysis showed the reaction to be complete. The reaction was pouredinto ice water (600 mL) and ether (500 mL) was added. Hexane (1.0 L) wasadded and the layers were separated. The aqueous layer was furtherextracted with Et₂O: hexane (1:2) (750 mL). The organic layers werechecked for product then discarded. ethyl acetate (500 mL) was added tothe aqueous layer, acidified to pH=2 with conc. HCl (18 mL), and thelayers were separated. The aqueous layer was extracted with ethylacetate (2×200 mL). The organic layer was dried over NaCl and solventremoved in vacuo to provide 50.0 g of crude product. The product wasused in the next step without further purification: ¹H NMR (400 MHz,CDCl₃) δ 7.33 (dd, 1H), 7.26 (m, 2H), 7.12 (m, 1H), 7.04 (d, 1H), 6.97(m, 2H), 6.87 (dd, 1H), 5.37 (s, 1H), 1.40 (s, 3H); MS (EI−) 277.1(M−1)⁻.

Step B 2-Methyl-2-phenoxy-3-thiophen-2-yl-propionic acid

To a solution of triethylsilane (56.4 g, 77.4 mL, 485 mmol) in 100 mL ofCH₂Cl₂ at −20° C., boron trifluoride diethyl etherate (68.8 g, 61.5 mL,485 mmol) was added. A solution of3-hydroxy-2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (45.0 g, 162mmol) in CH₂Cl₂ (600 mL) was then added dropwise to the BF₃ solutionover 1 h, keeping the temperature at −15° C. The reaction was stirred at0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 360 mL)diluted with 180 mL of water and the pH was adjusted to pH=4.0 using 1 NHCl and 1 N NaOH. The organic layer was separated and the aqueous layerwas further extracted with CH₂Cl₂ (2×300 mL). The combined organiclayers were then washed with 0.1 N HCl (300 mL) and water (2×300 mL).Xylene (150 mL) and NaCl were added and the organics were concentratedto dryness to yield 40.0 g of crude product. The product was used in thenext step without further purification: ¹H NMR (400 MHz, CDCl₃) δ6.86-7.29 (m, 8H), 3.53 (d, 2H), 3.37 (d, 2H), 1.44 (s, 3H); MS (EI)263.1 (M+H)⁺.

Step C 2-Methyl-2-phenoxy-3-thiophen-2-yl-propionic acid methyl ester

In a 100 mL beaker, 1.12 g of 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)was added to a solution of ether (30 mL) and 5 N KOH (2.3 mL) andstirred until N₂ evolution ceased. In another beaker, crude2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (1.00 g) was dissolvedin CH₂Cl₂ (20 mL). The beaker containing the ether/base mixture was thenplaced in a Dewar flask containing dry ice/acetone, the aqueous layerwas frozen and the ether layer decanted into the other beaker containingthe crude acid solution. This mixture was then stirred for an additional5 min, which by HPLC showed the reaction to be complete. The solvent wasremoved in vacuo to provide a crude oil. Purification by flashchromatography EtOAc: hexane (1:10) provided 533 mg of desired product(28%): ¹H NMR (400 MHz, CDCl₃) • 7.16-7.22 (m, 4H), 6.96 (m, 1H), 6.91(m, 1H), 6.84 (m, 2H), 3.73 (s, 3H), 3.49 (d, 1H), 3.38 (d, 1H), 1.42(s, 3H); MS (EI) 277.1 (M+H)⁺.

Step D 3-(5-Methyl-2-phenyl-oxazol-4-yl)-propionitrile

Toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester(5.00 g, 14.0 mmol), sodium cyanide (852 mg, 16.8 mmol), and potassiumbicarbonate (1.70 g, 16.8 mmol) were combined and vigorously stirred inDMSO (50 mL) at 50° C. for 2 h, then overnight at 25° C. The mixture wasthen poured into H₂O (50 mL) and extracted with Et₂O (2×50 mL). Theorganic layer were combined then washed with H₂O (50 mL), sat. NaCl (50mL), dried over NaCl. The solvent was removed in vacuo to provide 2.90 g(98%) of product as a white powder: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (m,2H), 7.39 (m, 3H), 2.81 (t, 2H), 2.71 (t, 2H), 2.35 (s, 3H); MS (EI)213.1 (M+H)⁺.

Step E 3-(5-Methyl-2-phenyl-oxazol-4-yl)-propionic acid

A mixture of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propionitrile (3.4 g,16.0 mmol) and HCl (10 mL) was stirred at 95° C. for 4.5 h. The reactionmixture was cooled to room temperature, poured into ice water (50 mL).The product was extracted with a 1:1 mixture of Et₂O and EtOAc (2×50mL). The combined organic layers were washed with sat. NaCl (50 mL),dried over NaCl, and solvent removed in vacuo to afford 2.27 g (61%) ofacid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (m, 2H), 7.40 (m,3H), 2.78 (t, 2H), 2.76 (t, 2H), 2.32 (s, 3H); MS (EI) 232.0 (M+H)⁺.

Step F2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionicacid methyl ester

A sample of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propionic acid (2.27 g,9.82 mmol) was dissolved in anhydrous CH₂Cl₂ (20 mL) followed byaddition of a catalytic amount of DMF (0.72 mL) and slow addition of a 2M solution of oxalyl chloride (7.36 mL). The reaction mixture wasstirred at room temperature for 24 h under N₂. The solvent was removedin vacuo to provide crude acid chloride which was then dissolved in 10mL anhydrous CH₂Cl₂ and then added to a flask containing2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid methyl ester (527167)(2.51 g, 9.11 mmol) in anhydrous CH₂Cl₂ (10 mL) at 0° C. under N₂.Anhydrous 1.0 M SnCl₄ solution (5.6 mL) was then added dropwise at 0° C.After 1 h, the reaction was checked by HPLC, it appeared that littleproduct had formed. Another 3.3 mL of SnCl₄ solution was added andallowed to stir for 24 h at room temperature. When the startingmaterials were consumed, the reaction was quenched by adding 6 M HCldropwise at 0° C. until solid forms (20 mL) and the aqueous phase wasextracted with CH₂Cl₂ (2×50 mL). The organic layer was washed with water(50 mL) and solvent removed to give an oil. Following columnchromatography (gradient 5% to 20% EtOAc in hexane), 1.31 g (30%) ofproduct was obtained: ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, 2H), 7.56 (d,1H), 7.38 (m, 3H), 7.20 (m, 2H), 6.84 (t, 1H), 6.81 (m, 3H), 3.72 (s,3H), 3.50 (d, 1H), 3.33 (d, 1H), 3.28 (t, 2H), 2.89 (t, 2H), 2.33 (s,3H), 1.41 (s, 3H); MS (EI) 490.2 (M+H)⁺.

Step G2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionicacid (515337)

Hydrolysis, using the procedure of Example 1, Step E, provided 275 mg(94%) of product from 300 mg of2-methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionicacid methyl ester: ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 2H), 7.60 (d, 1H),7.42 (m, 3H), 7.20 (m, 2H), 6.84 (t, 1H), 6.81 (m, 3H), 3.50 (d, 1H),3.35 (t, 2H), 3.33 (d, 1H), 2.95 (t, 2H), 2.40 (s, 3H), 1.41 (s, 3H); MS(EI) 476.0 (M+H)⁺.

Example 912-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionicacid

Step A3-{(5-[1-Hydroxy-3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-methyl-2-phenoxy-propionicacid methyl ester

A sample of2-methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propionyl]-thiophen-2-yl}-2-phenoxy-propionicacid methyl ester (1.00 g, 2.04 mmol) was dissolved in THF (40 mL) andMeOH (20 mL) and cooled to 0° C. Sodium borohydride (115 mg, 3.06 mmol)was added and allowed to stir at. 0° C. for 45 min. The reaction wasmonitored by HPLC. Upon the completion of the reaction, the bulk of thesolvent was removed in vacuo and water (40 mL) was added. The mixturewas acidified with 6 N HCl (20 mL) and stirred for 30 min. This aqueousmixture was then extracted with CH₂Cl₂ (2×50 mL). The organic fractionswere combined, dried over NaCl, and solvent removed in vacuo to give acrude oil. Flash chromatography (gradient 20% to 40% EtOAc in hexane)provided 650 mg (65%) of desired product: ¹H NMR (400 MHz, CDCl₃) δ 8.02(d, 2H), 7.47 (m, 3H), 7.19 (m, 2H), 6.96 (t, 1H), 6.79 (m, 3H), 6.68(d, 2H), 4.96 (m, 1H), 3.72 (s, 3H), 3.43 (d, 1H), 3.29 (d, 1H), 2.71(m, 2H), 2.30 (s, 3H), 2.17 (m, 2H), 1.42 (s, 3H); MS (EI) 492.2 (M+H)⁺.

Step B2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionicacid methyl ester

To a solution of triethylsilane (0.62 mL, 3.89 mmol) in CH₂Cl₂ (4 mL) at−20° C., boron trifluoride diethyl etherate (0.49 mL, 3.89 mmol) wasadded. A solution of3-{5-[1-hydroxy-3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-methyl-2-phenoxy-propionicacid methyl ester (650 mg, 1.30 mmol) in CH₂Cl₂ (4 mL) was then addeddropwise to the BF₃ solution over 1 h, keeping the temperature at −15°C. The reaction was stirred at 0° C. for 2 h. The reaction was quenchedwith 1 N NaOH (approx. 3.6 mL) diluted with 1.8 mL of water and the pHwas adjusted to pH 4.0 using 1 N HCl and 1 N NaOH. The organic layer wasseparated and the aqueous layer was further extracted with CH₂Cl₂ (2×30mL). The combined organic layers were then washed with 0.1 N HCl (30 mL)and water (2×30 mL). Xylene (15 mL) and NaCl were added and the organicswere concentrated to dryness to yield a yellow oil. The product was usedin the next step without further purification: ¹H NMR (400 MHz, CDCl₃) δ7.95 (d, 2H), 7.37 (m, 4H), 7.20 (m, 1H), 6.96 (t, 1H), 6.84 (d, 2H),6.60 (dd, 2H), 3.72 (s, 3H), 3.41 (d, 1H), 3.30 (d, 1H), 2.78 (t, 2H),2.50 (t, 2H), 2.24 (s, 3H), 2.00 (m, 2H), 1.43 (s, 3H); MS (EI) 476.2(M+H)⁺.

Step C2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionicacid

2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionicacid methyl ester 400 mg) was dissolved in EtOH (10 mL), and then 5 NNaOH (3 mL) was added. This mixture was allowed to stir at 60° C. for 1h. The mixture was cooled to room temperature and then acidified to pH=2by the dropwise addition of 5 N HCl. This acidic mixture was dilutedwith H₂O (10 mL) and then extracted with CH₂Cl₂ (2×25 mL). The organiclayers were combined, dried over NaCl, and solvent removed in vacuowhich provided 354 mg (92%) of desired acid: ¹H NMR (400 MHz, CDCl₃) δ8.05 (d, 2H), 7.39 (m, 4H), 7.23 (m, 1H), 7.03 (t, 1H), 6.95 (d, 2H),6.70 (d, 1H), 6.62 (d, 1H), 3.40 (d, 1H), 3.30 (d, 1H), 2.80 (t, 2H),2.52 (t, 2H), 2.27 (s, 3H), 2.02 (m, 2H), 1.44 (s, 3H); MS (EI) 462.2(M+H)⁺.

Example 922-(2-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz, CDCl₃):• 7.99-7.97 (m, 2H), 7.47 (dd, 3H, J=5.08 Hz, 1.96 Hz), 7.18 (d, 2H,J=8.60), 7.07 (td, 1H, J=6.65 Hz, 1.56 Hz), 6.89-6.80 (m, 4H), 6.63 (dd,1H, J=7.82 Hz, 1.56 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d,1H, J=14.1 Hz), 3.10-3.04 (m, 3H), 2.41 (s, 3H), 1.30 (s, 3H). MS [ES+]m/z exact mass calcd for C₂₉H₃₀NO₆ 488.2073, found 488.2086.

Example 932-(2-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃): • 7.72 (d, 1H, J=3.52 Hz), 7.45 (d, 1H, J=3.52 Hz), 7.18 (d, 2H,J=8.60 Hz), 7.12-7.05 (m, 2H), 6.88 (d, 1H, J=7.82 Hz), 6.84-6.79 (m,3H), 6.62 (d, 1H, J=6.65 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.82 (s, 3H),3.30 (d, 1H, J=14.08 Hz), 3.08 (d, 1H, J=14.08 Hz), 3.00 (t, 2H, J=6.26Hz), 2.37 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd forC₂₇H₂₈NO₆S 494.1637, found 494.1640.

Example 943-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from3-(4-Hydroxyphenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethylester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃): δ 7.18 (d, 2H, J=8.21 Hz), 7.06 (t, 1H, J=7.82 Hz), 6.88 (d, 1H,J=8.21 Hz), 6.83-6.79 (m, 3H), 6.62 (d, 1H, J=7.82 Hz), 4.12 (t, 2H,J=6.65 Hz), 3.82 (s, 3H), 3.29 (d, 1H, J=14.08 Hz), 3.09 (d, 1H, J=14.08Hz), 2.85 (t, 2H, J=6.65 Hz), 2.70-2.63 (m, 1H), 2.21 (s, 3H), 1.99 (d,2H, J=12.51 Hz), 1.77 (d, 2H, J=12.90 Hz), 1.67 (d, 1H, J=11.73 Hz),1.50 (q, 2H, J=12.51 Hz), 1.37-1.21 (m, 5H). MS [ES+] m/z exact masscalcd for C₂₉H₃₆NO₆ 494.2543, found 494.2562.

Example 952-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-o-tolyloxy-propionicacid

Step A 2-o-Tolyloxy-propionic acid ethyl ester

Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of2-cresol (10.0 g, 92.5 mmol) in anhydrous DMF (500 mL) at roomtemperature under an atmosphere of nitrogen. After five minutes, ethyl2-bromopropionate (16.7 mL, 92.5 mmol, d=1.394) was added rapidlydropwise and the resultant mixture was allowed to stir at 90° C. for 18h. The reaction mixture was diluted with diethyl ether, then extractedtwice with 1N HCl and twice with water. The organic layer was dried overMgSO₄ and concentrated in vacuo to provide the title compound (19.7 g,100%). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, 1H, J=7.43 Hz), 7.11 (t, 1H,J=7.43 Hz), 6.89 (t, 1H, J=7.48 Hz), 6.70 (d, 1H, J=7.43 Hz), 4.75 (q,1H, J=6.65 Hz), 4.23 (q, 2H, J=6.65 Hz), 2.30 (s, 3H), 1.64 (dd, 3H,J=7.04 Hz, 0.78 Hz), 1.26 (td, 3H, J=7.04 Hz, 0.78 Hz). R_(f)=0.3⁷ in25% ether in hexanes.

Step B 3-(4-Benzyloxy-phenyl)-3-hydroxy-2-methyl-2-o-tolyloxy-propionicacid ethyl ester

A solution of LDA (34.9 mL, 52.4 mmol, 1.5M in cyclohexane) in anhydrousTHF (60 mL) was cooled to −78° C. in a dry ice/acetone bath and added toa solution of 2-o-Tolyloxy-propionic acid ethyl ester in anhydrous THF(60 mL) also cooled to −78° C. under an atmosphere of nitrogen. Afterfive minutes, 4-benzyloxybenzaldehyde (5.56 g, 26.2 mmol) was added inone portion. After stirring for one minute, the reaction mixture wasquenched with acetic acid (5 mL, 87.4 mmol, d=1.049) and a saturatedsolution of aqueous NH₄Cl (50 mL). The biphasic mixture was allowed towarm to room temperature and diluted with diethyl ether (1 L). Theorganic layer was washed with water, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash column chromatography (13%ethyl acetate in hexanes) to provide a mixture of diastereomers of thetitled compound (6.36 g, 54%). ¹H NMR (400 MHz, CDCl₃): • 7.44-7.32 (m,6H), 7.16-6.82 (m, 5H), 69.74-6.66 (m, 2H), 5.16 (d, 1H, J=3.52 Hz),5.07 (s, 2H), 4.26-4.15 (m, 2H), 2.28 (s, 3H), 1.43 (s, 3H), 1.22-1.17(m, 3H). R_(f)=0.25 in 25% ethyl acetate in hexanes.

Step C 3-(4-Benzyloxy-phenyl)-3-hydroxy-2-methyl-2-o-tolyloxy-propionicacid ethyl ester

3-(4-Benzyloxy-phenyl)-3-hydroxy-2-methyl-2-o-tolyloxypropionic acidethyl ester (6.36 g, 15.7 mmol) in anhydrous CH₂Cl₂ (140 mL) was cooledto 0° C. and treated with pyridine (13 mL, 157.2 mmol, d=0.987).Trifluoroacetic anhydride (6.7 mL, 47.2 mmol, d=1.487) was addeddropwise and the mixture was stirred for 2 h, gradually warming toambient temperature. The reaction mixture was diluted with diethyl etherand washed with 1N HCl, then water. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to produce the titled compound (7.4 g,91%) which was used without purification. ¹H NMR (400 MHz, CDCl₃): δ7.43-7.31 (m, 7H), 7.11 (d, 1H, J=7.43 Hz), 7.03-6.98 (m, 3H), 6.91 (t,1H, J=7.43), 6.69 (d, 1H, J=8.21 Hz), 6.34 (s, 1H), 5.08 (s, 2H),4.28-4.16 (m, 2H), 2.12 (s, 3H), 1.50 (s, 3H), 1.21 (td, 3H, J=7.04 Hz,0.78 Hz). R_(f)=0.55 in 25% ethyl acetate in hexanes.

Step D 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethylester

3-(4-Benzyloxy-phenyl)-2-methyl-2-o-tolyloxy-3-(2,2,2-trifluoro-acetoxy)-propionicacid ethyl ester (7.4 g, 14.3 mmol) was dissolved in ethyl acetate (300mL), treated with 5% palladium on carbon (7.4 g), and stirred under anatmosphere of hydrogen for 96 h. The suspension was filtered throughcelite and concentrated in vacuo to provide the titled compound (4.8 g,100%) as an opaque yellow oil.

¹H NMR (400 MHz, CDCl₃): • 7.14 (d, 1H, J=7.82 Hz), 7.07 t, 1H, J=8.60Hz), 7.01 (t, 1H, J=7.82 Hz), 6.84 (t, 1H, J=7.82 Hz), 6.72 (d, 2H,J=8.60 Hz), 6.60 (d, 1H, J=7.82 Hz), 5.96 (s, 1H), 4.19-4.15 (m, 2H),3.26 (d, 1H, J=13.69 Hz), 3.12 (d, 1H, J=13.69 Hz), 2.17 (s, 3H), 1.44(s, 3H), 1.18 (t, 3H, J=7.04 Hz). MS [ES+] m/z exact mass calcd forC₁₉H₂₆NO₄ 332.1862, found 332.1860.

Step E3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionicacid

Potassium carbonate (0.078 g, 0.56 mmol) was added to a solution of3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxypropionic acid ethyl ester andtoluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethylester in 4A sieve-dried ethanol (2 mL). The resultant mixture wasstirred at 80° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethanol (2 mL). 5N NaOH (0.5 mL) was added, then the reactionmixture was refluxed for 2 h. The reaction mixture was concentrated invacuo, diluted with 1N HCl, and extracted with CH₂Cl₂. The organic layerwas dried through a Varian ChemElut cartridge, concentrated in vacuo,and purified by LCMS. ¹H NMR (400 MHz, CDCl₃): • 7.96-7.92 (m, 2H), 7.40(t, 3H, J=3.13 Hz), 7.12 (d, 2H, J=6.65 Hz), 7.06 (t, 1H, J=7.82 Hz),6.91 (t, 1H, J=7.82 Hz), 6.80 (t, 4H, J=6.65 Hz), 4.17 (t, 2H, J=6.65Hz), 3.25 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.98 (t, 2H,J=6.65 Hz), 2.17 (s, 3H), 1.48 (s, 3H), 1.24 (s, 3H). MS [ES+] m/z exactmass calcd for C₂₉H₃₀NO₅ 472.2124, found 472.2129.

Example 962-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-o-tolyloxy-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from 3-(4-Hydroxyphenyl)-2-methyl-2-o-tolyloxy-propionicacid ethyl ester and toluene-4-sulfonic acid2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃): • 7.59 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.36 (dd, 1H, J=3.91 Hz,1.17 Hz), 7.14-7.11 (m, 3H), 7.08-7.04 (m, 2H), 6.91 (t, 1H, J=7.43 Hz),6.82-6.77 (m, 3H), 4.15 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz),3.19 (d, 1H, J=14.08 Hz), 2.94 (t, 2H, J=6.65 Hz), 2.33 (s, 3H), 2.17(s, 3H, 1.48 (s, 3H). MS [ES+] m/z exact mass calcd for C₂₇H₂₈NO₅S478.1688, found 478.1676.

Example 973-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-o-tolyloxy-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from 3-(4-Hydroxyphenyl)-2-methyl-2-o-tolyloxy-propionicacid ethyl ester and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. ¹H NMR (400 MHz,CDCl₃): δ 7.14-7.11 (m, 3H), 7.06 (t, 1H, J=7.82 Hz), 6.91 (t, 1H,J=7.82 Hz), 6.79 (d, 1H, J=8.60 Hz), 6.75 (d, 2H, J=8.60 Hz), 4.11 (t,2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.95(t, 2H, J=6.26 Hz), 2.90-2.87 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H),2.02-1.99 (m, 2H), 1.81-1.78 (m, 2H), 1.71-1.68 (m, 1H), 1.58-1.52 (m,2H), 1.47 (s, 3H), 1.38-1.21 (m, 5H). MS [ES+] m/z exact mass calcd forC₂₉H₃₆NO₅ 478.2593, found 478.2611.

Example 982-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-2-o-tolyloxy-propionicacid

The title compound was prepared using the representative StandardProcedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionicacid ethyl ester and Toluene-4-sulfonic acid2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethyl ester. ¹H NMR(400 MHz, CDCl₃): δ 7.14-7.11 (m, 3H), 7.08-7.04 (m, 1H), 6.91 (t, 1H,J=7.82 Hz), 6.81 (d, 1H, J=8.60 Hz), 6.76 (d, 2H, J=8.60 Hz), 4.10 (t,2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.93(t, 2H, J=6.26 Hz), 2.27 (s, 3H), 2.17 (s, 3H), 2.13-2.06 (m, 2H),1.54-1.48 (m, 8H), 1.40-1.34 (m, 3H), 1.27 (s, 3H). MS [EI+] 492 (M+H)⁺,[EI−] 490 (M−H)⁺.

Example 992-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

Step A 2-(3-Bromo-phenoxy)-propionic acid ethyl ester

Cesium carbonate (57.8 g, 177.4 mmol) was added to a solution of3-bromophenol (10.23 g, 59.1 mmol) in anhydrous DMF (500 mL) at roomtemperature under an atmosphere of nitrogen. After five minutes, ethyl2-bromopropionate (7.7 mL, 59.1 mmol, d=1.394) was added rapidlydropwise and the resultant mixture was allowed to stir at 90° C. for 18h. The reaction mixture was diluted with diethyl ether and extractedtwice with 1N HCl and three times with water. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (25% ether in hexanes) to provide the titledcompound (14.8 g, 97%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ7.13-7.07 (m, 3H), 7.02-7.13 (m, 1H), 6.79 (dt, 1H, J=7.63 Hz, 2.35 Hz),4.70 (q, 1H, J=6.75 Hz), 4.23 (q, 2H, J=3.52 Hz), 1.60 (d, 3H, J=7.04Hz), 1.24 (t, 3H, J=7.04 Hz). R=0.36 in 25% ether in hexanes.

Step B3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-3-hydroxy-2-methyl-propionicacid ethyl ester

A solution of LDA (39.7 mL, 59.5 mmol, 1.5M in cyclohexane) in anhydrousTHF (90 mL) was cooled to −78° C. in a dry ice/acetone bath and added toa solution of 2-(3-Bromo-phenoxy)-propionic acid ethyl ester inanhydrous THF (90 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After five minutes, 4-benzyloxybenzaldehyde (6.3 g, 29.8 mmol)was added in one portion. After stirring for one minute, the reactionmixture was quenched with acetic acid (5.7 mL, 99.2 mmol, d=1.049) and asaturated solution of aqueous NH₄Cl (80 mL). The biphasic mixture wasallowed to warm to room temperature and diluted with diethyl ether (1L). The organic layer was washed with water, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (17% ethyl acetate in hexanes) to provide a mixture ofdiastereomers of3-(4-Benzyloxyphenyl)-2-(3-bromo-phenoxy)-3-hydroxy-2-methyl-propionicacid ethyl ester (10.0 g, 62%). ¹H NMR (400 MHz, CDCl₃): • 7.42-7.28 (m,6H), 7.19-7.00 (m, 3H), 6.95 (dd, 2H, J=6.75 Hz, 1.76 Hz), 6.73 (dd, 1H,J=6.45 Hz, 1.47 Hz), 5.21-5.02 (m, 3H), 4.24-4.14 (m, 2H), 4.08 (q, 2H,J=7.04 Hz), 3.39 (s, 1H), 1.23 (t, 3H, J=7.04 Hz). R_(f)=0.22 in 25%ethyl acetate in hexanes.

Step C 3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-2-methyl-propionicacid ethyl ester

3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-3-hydroxy-2-methyl-propionicacid ethyl ester (10.0 g, 20.7 mmol) was added slowly to a −20° C.solution of triethylsilane (9.9 mL, 62.0 mmol, d=0.728) and borontrifluoride etherate (15.3 mL, 124.0 mmol, d=1.154) in anhydrous CH₂Cl₂(370 mL). The mixture was stirred for 6 h, gradually warming to 0° C.The reaction mixture was quenched with a saturated solution of aqueoussodium carbonate and extracted with CH₂Cl₂. The organic layer was driedover Na₂SO₄, concentrated in vacuo, and purified by flash columnchromatography to provide the titled compound (3.7 g, 38%). ¹H NMR (400MHz, CDCl₃): δ 7.46-7.33 (m, 5H), 7.18 (d, 2H, J=8.60 Hz), 7.15-7.05 (m,3H), 6.94 (dt, 2H, J=8.60 Hz), 6.78 (dt, 1H, J=7.82 Hz, 2.35 Hz), 4.23(q, 2H, J=7.04 Hz), 3.28 (d, 1H, J=13.69 Hz), 3.19 (d, 1H, J=13.69 Hz),1.45 (s, 3H), 1.23 (t, 3H, J=7.04 Hz). R_(f)=0.46 in 25% ethyl acetatein hexanes.

Step D 2-(3-Bromo-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidethyl ester

3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-2-methyl-propionic acid ethylester (3.7 g, 7.8 mmol) was dissolved in ethanol (140 mL), treated with5% palladium on carbon (0.37 g), and stirred under an atmosphere ofhydrogen for 2 h. The suspension was filtered through celite andconcentrated in vacuo. The residue was purified by flash columnchromatography (25% ethyl acetate in hexanes) to provide a mixture ofthe title compound and 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester as a light yellow oil (2.8 g, 94%). ¹H NMR (400 MHz,CDCl₃): δ 7.24-6.94 (m, 4H), 6.83-6.80 (m, 1H), 6.75-6.71 (m, 3H), 5.12(s, 1H), 4.19 (q, 2H, J=7.04 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.06 (d, 1H,J=13.69 Hz), 1.40 (s, 3H), 1.26-1.17 (m, 3H). MS [EI−] 377 (M−H)⁺.R_(f)=0.24 in 25% ethyl acetate in hexanes.

Step E2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester

Cesium carbonate (2.98 g, 9.2 mmol) was added to a solution of2-(3-Bromo-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester, 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethylester, and toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester in DMF (60 mL). Theresultant mixture was stirred at 65° C. under an atmosphere of nitrogenfor 18 h, then diluted with diethyl ether. The organic layer was washedwith 1N HCl and water, dried over MgSO₄, concentrated in vacuo, andpurified by flash column chromatography (9% acetone in hexanes) toprovide an unseparated mixture of2-(3-Bromophenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester and3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester (3.3 g, 80%). ¹H NMR (400 MHz, CDCl₃): δ 7.24-6.92 (m,5H), 6.81-6.69 (m, 3H), 4.20-4.10 (m, 5H), 3.22 (d, 1H, J=13.69 Hz),3.10 (d, 1H, J=13.69 Hz), 2.84 (t, 2H, J=6.65 Hz), 2.66 (tt, 1H, J=11.73Hz, 3.52 Hz), 2.21 (s, 3H), 2.01 (d, 2H, J=13.30 Hz), 1.79-1.75 (m, 2H),1.66 (d, 1H, J=11.73 Hz), 1.55-1.17 (m, 6H). MS [EI+] 571 (M+H)⁺.

Step F2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid

5N NaOH (0.5 mL) was added to a solution of2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester and3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester in ethanol (4 mL). The resultant mixture was refluxedunder an atmosphere of nitrogen for 2 h, then cooled to ambienttemperature. The reaction mixture was concentrated in vacuo, dilutedwith 1N HCl, and extracted with CH₂Cl₂. The organic layer was driedthrough a Varian ChemElut cartridge, concentrated in vacuo, and purifiedby LCMS. ¹H NMR (400 MHz, CDCl₃): δ 7.17 (m, 5H), 6.90-6.76 (m, 3H),4.12 (t, 2H, J=6.26 Hz), 3.22 (d, 1H, J=13.69 Hz), 3.10 (d, 1H, J=13.69Hz), 2.95 (t, 2H, J=6.26 Hz), 2.90-2.68 (m, 1H), 2.30 (s, 3H), 2.01 (d,2H, J=13.30 Hz), 1.79 (d, 2H, J=12.90 Hz), 1.69 (d, 1H, J=13.30 Hz),1.40 (s, 3H), 1.58-1.21 (m, 4H). MS [EI+] 543 (M+H)⁺.

Example 1003-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionicacid

Step A3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionicacid ethyl ester

Add palladium acetate (8 mg, 0.04 mmol) to a solution of2-(3-Bromo-phenoxy)-3-(4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid (0.204 g, 0.36 mmol), thiophene-3-boronic acid (91 mg, 0.71 mmol),triphenylphosphine (19 mg, 0.07 mmol), and potassium fluoride (51 mg,1.07 mmol) in anhydrous THF (3 mL). Reflux the reaction mixture for 18 hunder an atmosphere of nitrogen. Dilute the cooled reaction mixture withethyl acetate and wash with water and brine. The organic layer was driedover Na₂SO₄, concentrated in vacuo, and purified by flash columnchromatography (9% acetone in hexanes) to provide a mixture of thetitled compound and3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester (70 mg, 34%). ¹H NMR (400 MHz, CDCl₃): δ 7.38-7.19 (m,5H), 7.13 (d, 2H, J=8.60 Hz), 7.07 (m, 1H), 6.80 (2H, J=8.60 Hz),6.73-6.70 (m, 1H), 4.19 (q, 2H, J=7.04 Hz), 4.12 (t, 2H, J=6.65 Hz),3.27 (d, 1H, J=13.69 Hz), 3.11 (d, 1H, J=13.69 Hz), 2.85 (t, 2H, J=6.65Hz), 2.70-2.63 (m, 1H), 2.22 (s, 3H), 2.01 (d, 2H, J=11.73 Hz),1.79-1.76 (m, 2H), 1.67 (h, 1H, J=11.73 Hz), 1.59 (s, 3H), 1.56-1.46 (m,2H), 1.41 (s, 3H), 1.37-1.23 (m, 2H), 1.20 (t, 3H, J=7.04 Hz). MS [EI+]574 (M+H)⁺. R_(f)=0.08 in 9% ethyl acetate in hexanes.

Step B3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionicacid

5N NaOH (0.5 mL) was added to a solution of3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionicacid ethyl ester and3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy-]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester in ethanol (4 mL). The resultant mixture was refluxedunder an atmosphere of nitrogen for 2 h, then cooled to ambienttemperature. The reaction mixture was concentrated in vacuo, dilutedwith 1N HCl, and extracted with CH₂Cl₂. The organic layer was driedthrough a Varian ChemElut cartridge, concentrated in vacuo, and purifiedby LCMS. ¹H NMR (400 MHz, CDCl₃): δ 7.39-7.26 (m, 5H), 7.17 (d, 2H,J=8.60 Hz), 7.11-7.10 (m, 1H), 6.82-6.80 (m, 1H), 6.78 (d, 2H, J=8.60Hz), 4.11 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H,J=14.08 Hz), 2.93 (t, 2H, J=6.26 Hz), 2.87-2.81 (m, 1H), 2.28 (s, 3H),1.99 (d, 2H, J=12.51 Hz), 1.77 (d, 2H, J=12.51), 1.67 (d, 2H, J=12.51),1.57-1.46 (m, 2H), 1.45 (s, 3H), 1.37-1.19 (m, 2H). MS [ES+] m/z exactmass calcd for C₃₂H₃₆NO₅S 546.2314, found 546.2308.

Example 1012-(Biphenyl-3-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester

Step A2-(Biphenyl-3-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester

Add palladium acetate (8 mg, 0.04 mmol) to a solution of2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid (0.204 g, 0.36 mmol), thiophene-3-boronic acid (91 mg, 0.71 mmol),triphenylphosphine (19 mg, 0.07 mmol), and potassium fluoride (51 mg,1.07 mmol) in anhydrous THF (3 mL). Reflux the reaction mixture for 18 hunder an atmosphere of nitrogen. Dilute the cooled reaction mixture withethyl acetate and wash with water and brine. Dry the organic layer overNa₂SO₄, concentrate in vacuo, and purify by flash column chromatography(9% acetone in hexanes) to provide a mixture of the titled compound and3-[4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester. ¹H NMR (400 MHz, CDCl₃): δ 7.53 (d, 1H, J=7.04 Hz),7.41 (t, 1H, J=7.82 Hz), 7.35-7.13 (m, 6H), 7.08-6.95 (m, 1H), 6.81 (s,4H), 4.22-4.13 (m, 4H), 3.26 (d, 1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08Hz), 2.87-2.66 (m, 3H), 2.23 (s, 3H), 2.02 (d, 2H, J=11.23 Hz), 1.80 (m,10H), 1.21 (t, 3H, J=7.04 Hz). MS [EI+] 568 (M+H)⁺. R_(f)=0.14 in 25%acetone in hexanes.

Step B2-(Biphenyl-3-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl)}-2-methyl-propionicacid

5N NaOH (0.5 mL) was added to a solution of2-(Biphenyl-3-yloxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionicacid ethyl ester and3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester in ethanol (4 mL). The resultant mixture was refluxedunder an atmosphere of nitrogen for 2 h, then cooled to ambienttemperature. The reaction mixture was concentrated in vacuo, dilutedwith 1N HCl, and extracted with CH₂C1₂. The organic layer was driedthrough a Varian ChemElut cartridge, concentrated in vacuo, and purifiedby LCMS. ¹H NMR (400 MHz, CDCl₃): δ 7.51 (d, 2H, J=7.82 Hz), 7.41 (t,2H, J=7.04 Hz), 7.35-7.24 (m, 2H), 7.18 (d, 3H, J=8.21 Hz), 7.12-7.11(m, 1H), 6.86 (d, 1H, J=8.60 Hz), 7.82 (d, 2H, J=8.60 Hz), 4.13 (t, 2H,J=5.47 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08 Hz), 2.95 (t,3H, J=5.47 Hz), 2.29 (s, 3H), 2.00 (d, 2H, J=12.51 Hz), 1.79 (d, 2H,J=13.30 Hz), 1.70-1.21 (m, 8H). MS [EI+] 540 (M+H)⁺.

Example 1042-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(quinolin-6-yloxy)-propionicacid Step A 2-(Quinolin-6-yloxy)-propionic acid ethyl ester

A mixture of 2-bromo-propionic acid ethyl ester (14.6 mL, 0.112 mol),quinolin-6-ol (16.3 g, 0.112 mol) and Cs₂CO₃ (44 g, 0.135 mol) in 500 mLof DMF was heated to 90° C. for overnight. The mixture was filtered anddiluted with Et₂O (500 mL). Organic layer was washed with water andbrine. The combined aqueous layer was then extracted with EtOAc.Combined organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated. Crude material was purified bychromotography (R_(f)=0.3 in hexanes/acetone=1:1) to give 22 g of titlecompound as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δδ 8.78 (dd, 1H,J=4.0, 0.8 Hz), 8.02 (d, 1H, J=8.8 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.42(dd, 1H, J=9.4, 3.0 Hz), 7.35 (dd, 1H, J=8.6, 4.2 Hz), 7.26 (d, 1H,J=1.2 Hz), 6.99 (d, 1H, J=2.8 Hz), 4.89 (q, 1H, J=6.8 Hz), 4.27-4.20 (m,2H), 1.69 (d, 3H, J=6.8 Hz), 1.24 (t, 3H, J=6.8 Hz).

Step B 3-(4-Benzyloxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionicacid ethyl ester

To a LDA solution (42 mL, 1.5 M solution in THF) in 65 mL of dry THF at−78° C., a solution of 2-(quinolin-6-yloxy)-propionic acid ethyl ester(8.61 g, 0.035 mol) in 65 mL of dry THF was cannulated in. The resultingsolution is allowed to stand at −78° C. for 3 min. Solid4-benzyloxybenzaldehyde (6.71 g, 0.032 mol) was added and resultingmixture was allowed to stand at −78° C. for 5 min until all soliddissovled in the solution. Reaction was then quenched with AcOH (6.03mL, 0.105 mol) in 60 mL of THF at −78° C. The mixture was then dilutedwith Et₂O and washed with sat'NH4Cl, water and brine, dried over Na₂SO₄,filtered and concentrated. The crude material was purified bychromatography to give3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionicacid ethyl ester in 86% yield. A of solution of 2.75 g of give3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionicacid ethyl ester (6.01 mmol), trifluoroacetic acid (2.8 mL, 36.1 mmol),triethylsilane (5.8 mL, 36.1 mmol) in 80 mL of dichloroethane was heatedto reflux for 50 h. The mixture was cooled to r.t. and diluted with Et₂Oand washed with sat′ NaHCO₃, water and brine. Organic layer was driedover Mg SO₄, filtered and concentrated. Residue was purified bychromatography (5% MeOH in CH₂Cl₂) to give 86% of title compound aslight yellow oil. ¹H NMR (400 MHz, CDCl₃) δδ 8.78 (dd, 1H, J=4.4, 1.6Hz), 8.00 (d, 1H, J=9.2 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.45-7.32 (m, 7H),7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 6.93 (d, 2H, J=8.8 Hz),5.06 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 3.38, 3.18 (ABq, 2H, J=13.8 Hz),1.53 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES⁺) m/z mass calcd forC₂₈H₂₈NO₄ (m+1) 442, found 442.

Step C 3-(4-Hydroxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acidethyl ester

A solution of3-(4-Benzyloxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acidethyl ester (2.65 g, 6.0 mmol) in 100 mL of EtOH with 5% Pd/C (530 mg,20 w %) was allowed to stand under 1 atm H2 for 6 h. Catalyst wasfiltered off and organic solvent was removed under vacuum. Residue wasthen dissolved in 200 mL of toluene. 530 mg of 10% Pd/C was added. Themixture was heated to reflux under air for overnight. Reaction wascooled to r.t. and catalyst was filtered off. Organic solvent wasremoved under vacuum and crude material was clean for next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δδ 8.77 (dd, 1H, J=4.0,1.4 Hz), 8.04 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=9.6 Hz), 7.38 (dd, 1H,J=8.4, 4.4 Hz), 7.32 (dd, 1H, J=9.2, 2.8 Hz), 7.09 (d, 2H, J=8.8 Hz),7.03 (d, 1H, J=2.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.22 (q, 2H, J=7.1 Hz),3.35, 3.13 (ABq, 2H, J=13.6 Hz), 1.52 (s, 3H), 1.19 (t, 3H, J=7.1 Hz).MS (ES⁺) m/z mass calcd for C₂₁H₂₂NO₄ (m+1) 352, found 352.

Step D2-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(quinolin-6-yloxy)-propionicacid

A solution of toluene-4-sulfonic acid2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (94 mg, 0.26 mmol),3-(4-Hydroxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethylester (77.3 mg, 0.22 mmol) and K2CO3 (61 mg, 0.44 mmol) in 2 mL of EtOHwas heated to 80° C. for overnight. Then 5N NaOH (0.26 mL, 1.3 mmol) wasadded and reaction mixture was stand at same temperature for 2 h. Themixture was cooled off to r.t. and organic solvent was removed undervacuum. Residue was then dissolved in CH₂Cl₂ and 1N HCl. Aqueous layerwas washed with CH₂Cl₂ (2×). Combined organic layer was washed withbrine, dried over Na2SO4, filtered and concentrated. Residue waspurified by MS/LC to give title compound as white solid (55.6 mg, 50%).¹H NMR (400 MHz, CDCl₃) δδ 8.76 (d, 1H, J=4.4 Hz), 8.28 (d, 1H, J=8.4Hz), 7.94 (d, 1H, J=9.2 Hz), 7.89-7.87 (m, 2H), 7.51-7.45 (m, 3H),7.38-7.32 (m, 2H), 7.25-7.23 (m, 1H), 7.20 (d, 1H, J=2.4 Hz), 7.16 (d,2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.17 (t, 2H, J=6.6 Hz), 3.29,3.11 (ABq, 2H, J=13.4 Hz), 2.90 (t, 2H, J=6.6 Hz), 2.33 (s, 3H), 1.42(s, 3H). HRMS (ES⁺) m/z exact mass calcd for C₃₁H₂₉N₂O₅ (m+1) 509.2076,found 509.2095.

Example 1053-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(quinolin-6-yloxy)-propionicacid

A solution of Toluene-4-sulfonic acid2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (96 mg, 0.26 mmol),3-(4-Hydroxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethylester (77.3 mg, 0.22 mmol) and K₂CO₃ (61 mg, 0.44 mmol) in 2 mL of EtOHwas heated to 80° C. for overnight. Then 5N NaOH (0.26 mL, 1.3 mmol) wasadded and reaction mixture was stand at same temperature for 2 h. Themixture was cooled off to r.t. and organic solvent was removed undervacuum. Residue was then dissolved in CH₂Cl₂ and 1N HCl. Aqueous layerwas washed with CH₂Cl₂ (2×). Combined organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. Residue waspurified by MS/LC to give title compound as white solid (54.5 mg, 48%).¹H NMR (400 MHz, CDCl₃) δδ 8.74 (dd, 1H, J=4.0, 1.6 Hz), 8.24 (d, 1H,J=6.8 Hz), 7.92 (d, 1H, J=9.2 Hz), 7.45 (dd, 1H, J=8.2, 4.2 Hz), 7.33(dd, 1H, J=5.2, 2.8 Hz), 7.19 (d, 1H, J=2.8 Hz), 7.15, 6.82 (ABq, 4H,J=8.6 Hz), 4.08 (t, 2H, J=6.8 Hz), 3.29, 3.11 (ABq, 2H, J=13.8 Hz), 2.76(t, 2H, J=6.8 Hz), 2.68-2.63 (m, 1H), 2.18 (s, 3H), 1.93-1.87 (m, 2H),1.71-1.65 (m, 2H), 1.62-1.57 (m, 1H), 1.46-1.14 (m, 5H), 1.42 (s, 3H).HRMS (ES⁺) m/z exact mass calcd for C₃₁H₃₅N₂O₅ (m+1) 515.2546, found515.2567.

Additional compounds of the present invention, having the structuralformula shown below, were synthesized by methods similar to thosedescribed in the previous examples.

These additional compounds are further exemplified in the followingtable.

TABLE I Example R9 R6 R3 R7 meta R8 para R8 92 phenyl H CH3 H H OCH3 93cyclohexyl H CH3 H t-butyl H 94 phen-butyl H CH3 H H H 95 phenyl OCH3CH3 H H H 96 morpholino H CH3 H H H 97 phenethyl H CH3 H H H 98phenethyl H CH3 H H t-butyl 99 phenethyl H CH3 H H F 100 phenethyl H CH3H OCH3 H 101 phenethyl H CH3 H CH3 H 102 phenethyl H CH3 H CF3 H 103phenethyl H CH3 H H CF3 104 phenethyl H CH3 H F H 105 phenethyl H CH3 HH Cl 106 phenethyl H C2H5 H H H 107 phenethyl H CH3 H H OCF3 108 benzylH CH3 H H F 109 benzyl H CH3 H OCH3 H 110 benzyl H CH3 H CH3 H 111benzyl H CH3 H CF3 H 112 benzyl H CH3 H H CF3 113 benzyl H CH3 H F H 114benzyl H CH3 H H Cl 115 benzyl H C2H5 H H H 116 benzyl H CH3 H H OCF3117

H CH3 H H H 118

H CH3 H H H 119 1-methyl- H CH3 H H CF3 cyclohexyl 120 3-thienyl H CH3 HH H 121 phenyl H CH3 OCH3 H H 122 2-thienyl H CH3 OCH3 H H 123cyclohexyl H CH3 OCH3 H H 124

H CH3 H H CH3 125 phenyl H CH3 CH3 H H 126 2-thienyl H CH3 CH3 H H 127cyclohexyl H CH3 CH3 H H 128 1-methyl- H CH3 CH3 H H cyclohexyl 129t-butyl H CH3 H H H 130

H CH3 H H CF3 131 cyclohexyl H CH3 H H t-butyl 132 morpholino H CH3 H Ht-butyl 133 cyclohexyl H CH3 H 3- H thienyl 134 cyclohexyl H CH3 Hphenyl H 135 cyclohexyl H CH3 H Br H 136 cyclohexyl H CH3 H H t-butyl137 phenyl H CH3 H Cl H 138 2-thienyl H CH3 H Cl H 139 1-methyl- H CH3 HCl H cyclohexyl 140 1-methyl- H CH3 F H H cyclohexyl

Other compounds of the present invention, having the structural formulashown below, were also synthesized by methods similar to those describedin the previous examples.

These additional compounds are further exemplified in the followingtable.

TABLE II Example R9 R4 141 phenyl quinolyl 142 2-thienyl quinolyl 143cyclohexyl quinolyl 144 phenyl 1,2,3,4-tetrahydronaphthyl 145 cyclohexyl1,2,3,4-tetrahydronaphthyl 146 1-methyl-cyclohexyl1,2,3,4-tetrahydronaphthyl 147 phenyl pyridyl

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARR• And PPAR•receptors were determined by the procedures detailed below.DNA-dependent binding (ABCD binding) was carried out using SPAtechnology with PPAR receptors. Tritium-labeled PPARα and PPARγ agonistswere used as radioligands for generating displacement curves and IC₅₀values with compounds of the invention. Cotransfection assays werecarried out in CV-1 cells. The reporter plasmid contained an acylCoAoxidase (AOX) PPRE and TK promoter upstream of the luciferase reportercDNA. Appropriate PPARs and RXRα were constitutively expressed usingplasmids containing the CMV promoter. For PPARα and PPARβ, interferenceby endogenous PPARγ in CV-1 cells was an issue. In order to eliminatesuch interference, a GAL4 chimeric system was used in which the DNAbinding domain of the transfected PPAR was replaced by that of GAL4, andthe GAL4 response element was utilized in place of the AOX PPRE.Cotransfection efficacy was determined relative to PPARα agonist andPPARγ agonist reference molecules. Efficacies were determined bycomputer fit to a concentration-response curve, or in some cases at asingle high concentration of agonist (10 μM). For binding orcotransfection studies with receptors other than PPARs, similar assayswere carried out using appropriate ligands, receptors, reporterconstructs, etc., for that particular receptor.

These studies were carried out to evaluate the ability of compounds ofthe invention to bind to and/or activate various nuclear transcriptionfactors, particularly huPPARα (“hu” indicates “human”) and huPPARγ.These studies provide in vitro data concerning efficacy and selectivityof compounds of the invention. Furthermore, binding and cotransfectiondata for compounds of the invention were compared with correspondingdata for marketed compounds that act on either huPPARα or huPPARγ.

Binding and cotransfection data for representative compounds of theinvention are compared with corresponding data for reference compoundsin Table III.

TABLE III Comparison of binding IC₅₀ values and cotransfection efficacydata of compounds of the invention to reference compounds. huPPARαhuPPARγ CTF CTF Efficacy Efficacy Example IC₅₀ (nm) (%) IC₅₀ (nM) (%) 140 70 10 79 2 1250 59 476 400 3 22 70 7 74 4 39 80 9 63 5 542 65 170 756 23 72 7 70 7 27 82 58 72 8 63 54 24 75 9 41 61 11 73 17 68 129 67 10518 72 102 60 112 19 85 64 80 23 22 70 51 85 12 23 63 40 81 17 25 73 9570 106 27 75 46 76 15 29 116 65 48 82 31 53 63 19 73 34 91 112 77 76 3566 78 79 21 36 72 70 88 21 40 50 77 10 110 41 66 49 109 11 44 157 54 15973 49 175 63 655 58 51 64 152 80 48 52 62 108 76 61 58 60 149 66 41 6164 52 84 12 62 58 101 79 35 64 67 50 112 11 65 71 46 82 24 67 61 34 6511 71 78 142 81 50 76 76 63 83 24 78 75 52 89 17 80 76 84 80 30 86 55 2472 7 88 58 61 16 78 91 215 47 51 62 Trogli- 94,500 0 1180 80 tazoneFeno- 68,000 16 125,000 0 fibric acid

Evaluation of Triglyceride and Cholesterol Level in HuapoAI TransgenicMice

Five to six week old male mice, transgenic for human apoAI [C57Bl/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.] were housed five percage (10″×20″×8″ with aspen chip bedding) with food (Purina 5001) andwater available at all times. After an acclimation period of 2 weeks,animals were individually identified by ear notches, weighed, andassigned to groups based on body weight. Beginning the followingmorning, mice were dosed daily by oral gavage for 7 days using a 20gauge, 1½″ curved disposable feeding needle (Popper & Sons). Treatmentswere test compounds (30 mg/kg), a positive control (fenofibrate, 100mg/kg) or vehicle [1% carboxyymethylcellulose (w/v)/0.25% Tween80 (w/v);0.2 ml/mouse]. Prior to termination on day 7, mice were weighed anddosed. Three hours after dosing, animals were anesthetized by inhalationof isoflurane (2-4%; Abbott Laboratories, Chicago, Ill.) and bloodobtained via cardiac puncture (0.7-1.0 ml). Whole blood was transferredto serum separator tubes (Vacutainer SST), chilled on ice, and permittedto clot. Serum was obtained after centrifugation at 4° C. and frozenuntil analysis for triglycerides, total cholesterol, compound levels,and serum lipoprotein profile by fast protein liquid chromatography(FPLC) coupled to an inline detection system. After sacrifice bycervical dislocation, the liver, heart and epididymal fat pads wereexcised and weighed.

The animals dosed with vehicle had average triglycerides values of 60-80mg/dl, which were reduced by the positive control fenofibrate (33-58mg/dl with a mean reduction of 37%). The animals dosed with vehicle hadaverage total serum cholesterol values of 140-180 mg/dl, which wereincreased by fenofibrate (190-280 mg/dl, with a mean elevation of 41%).Triglyceride serum levels for animals receiving compounds of theinvention are reported in Table IV in mg/dl. When subject to FPLCanalysis, pooled sera from vehicle-treated hu apoAI transgenic mice hada high density lipoprotein cholesterol (HDLc) peak area which rangedfrom 47 v-sec to 62 v-sec. Fenofibrate increased the amount of HDLc(68-96 v-sec with a mean percent increase of 48%). Test compounds arereported in terms of percent increase in the area under the curve asindicated in Table V.

TABLE IV Triglyceride serum levels in mice receiving a compound of theinvention. Reduction in Triglyceride Serum Level Example (Percent)  41.3  2 −12.9   4 58.3  5 19.7  6 38.5  7 42.1  9 19.8 17 78.7 18 69.019 40.0 22 19.5 23 52.5 25 35.5 27 36.8 34 57.1 35 32.3 36 23.0 40 77.641 57.8 51 72.8 52 75.9 58 26.5 61 17.6 62  2.5 64 43.0 65 54.0 67 67.876 27.1 78 64.8 80 36.6 86 30.1

TABLE V Percent increase of HDLc serum levels in mice receiving acompound of the invention over mice receiving vehicle Example % HDLcIncrease  1 83  2 25  3 67  4 24  5 30  6 85  7 39  8 34  9 123 17 11918 141 19 89 22 29 23 54 25 8 27 49 29 78 31 114 34 95 35 77 36 30 40131 41 96 44 151 49 17 51 122 52 185 58 74 61 72 62 72 64 66 65 75 67 7671 34 76 26 78 95 80 123 86 36 88 86 91 46

Evaluation of Glucose Levels in db/db Mice

Five week old male diabetic (db/db) mice [C57BlKs/j-m+/+Lepr (db),Jackson Laboratory, Bar Harbor, Me.] or lean littermates (db+) werehoused 6 per cage (10″×20″×8″ with aspen chip bedding) with food (Purina5015) and water available at all times. After an acclimation period of 2weeks, animals were individually identified by ear notches, weighed, andbled via the tail vein for determination of initial glucose levels.Blood was collected (100 μl) from unfasted animals by wrapping eachmouse in a towel, cutting the tip of the tail with a scalpel, andmilking blood from the tail into a heparinized capillary tube (Fisher)balanced on the edge of the bench. Sample was discharged into aheparinized microtainer with gel separator (VWR) and retained on ice.Plasma was obtained after centrifugation at 4° C. and glucose measuredimmediately. Remaining plasma was frozen until the completion of theexperiment, when glucose and triglycerides were assayed in all samples.Animals were grouped based on initial glucose levels and body weights.Beginning the following morning, mice were dosed daily by oral gavagefor 7 days using a 20 gauge, 1½″ curved disposable feeding needle.Treatments were test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse]. On day 7, mice were weighed and bled (tail vein) 3 hoursafter dosing. Twenty-four hours after the 7^(th) dose (i.e., day 8),animals were bled again (tail vein). Samples obtained from consciousanimals on days 0, 7 and 8 were assayed for glucose. After the 24 hourbleed, animals were weighed and dosed for the final time. Three hoursafter dosing on day 8, animals were anesthetized by inhalation ofisoflurane and blood obtained via cardiac puncture (0.5-0.7 ml). Wholeblood was transferred to serum separator tubes, chilled on ice andpermitted to clot. Serum was obtained after centrifugation at 4° C. andfrozen until analysis for compound levels. After sacrifice by cervicaldislocation, the liver, heart and epididymal fat pads were excised andweighed.

The animals dosed with vehicle had average triglycerides values of170-230 mg/dl, which were reduced by the positive PPARγ control (70-120mg/dl with a mean reduction of 50%). Male db/db mice were hyperglycemic(average glucose of 680-730 mg/dl on the 7^(th) day of treatment), whilelean animals had average glucose levels between 190-230 mg/dl. Treatmentwith the positive control agent reduced glucose significantly (350-550mg/dl with a mean decrease towards normalization of 56%). Test compoundsare reported in Table VI in terms of glucose normalization (i.e., 100%normalization would be glucose levels in treated db/db mice which didnot differ from lean values.

Glucose was measured colorimetrically using commercially purchasedreagents (Sigma #315-500). According to the manufacturers, theprocedures were modified from published work (McGowan, M. W., Artiss, J.D., Strandbergh, D. R. & Zak, B. Clin Chem, 20:470-5 (1974) and Keston,A. Specific colorimetric enzymatic analytical reagents for glucose.Abstract of papers 129th Meeting ACS, 31C (1956).); and depend on therelease of a mole of hydrogen peroxide for each mole of analyte, coupledwith a color reaction first described by Trinder (Trinder, P.Determination of glucose in blood using glucose oxidase with analternative oxygen acceptor. Ann Clin Biochem, 6:24 (1969)). Theabsorbance of the dye produced is linearly related to the analyte in thesample. The assays were further modified in our laboratory for use in a96 well format. Standards (Sigma #339-11, Sigma #16-11, and Sigma#CCO534 for glucose, triglycerides and total cholesterol, respectively),quality control plasma (Sigma #A2034), and samples (2 or 5 μl/well) weremeasured in duplicate using 200 μl of reagent. An additional aliquot ofsample, pipetted to a third well and diluted in 200 μl water, provided ablank for each specimen. Plates were incubated at room temperature (18,15, and 10 minutes for glucose, triglycerides and total cholesterol,respectively) on a plate shaker (DPC Micormix 5) and absorbance read at500 nm (glucose and total cholesterol) or 540 nm (triglycerides) on aplate reader (Wallac Victor 1420). Sample absorbances were compared to astandard curve (100800, 10-500, and 100-400 mg/dl for glucose,triglycerides and total cholesterol, respectively). Values for thequality control sample were always within the expected range and thecoefficient of variation for samples was below 10%. All samples from anexperiment were assayed at the same time to minimize inter-assayvariability.

Serum lipoproteins were separated and cholesterol quantitated with anin-line detection system. Sample was applied to a Superose® 6 HR 10/30size exclusion column (Amersham Pharmacia Biotech) and eluted withphosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol reagent (RocheDiagnostics Cho1/HP 704036) at 0.16 ml/min mixed with the columneffluent through a T-connection and the mixture passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37 C water bath. Thecolored product produced in the presence of cholesterol was monitored inthe flow stream at 505 nm and the analog voltage from the monitor wasconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration was plottedvs time and the area under the curve corresponding to the elution ofVLDL, LDL and HDL was calculated using Perkin Elmer Turbochromesoftware.

TABLE VI Percent glucose normalisation values in db/db mice. GlucoseExample Normalisation  1 95  2 9  3 85  4 74  5 80  6 86  7 86  8 97  995 17 112 18 110 19 95 22 85 23 97 25 73 27 86 29 86 34 80 35 84 36 9240 103 41 101 44 83 51 88 52 98 58 81 61 79 62 79 64 97 65 99 67 96 7197 76 97 78 86 80 83 86 92 88 92 91 71

Equivalents

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof wherein: (a) R1 is anunsubstituted or substituted thiophenyl, or thiophenyl-C1-C4 alkyl;wherein one or more substituents for thiophenyl or thiophenyl-C1-C4 areselected from the group consisting of: halo, carboxyl, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, cyano, CHO,hydroxyl, C1-C4 alkanoic acid and —C(O)NR13R13; and wherein each R13 isindependently H or a C1-C4 alkyl, (b) R2 is H, C1-C4 alkyl, C1-C4haloalkyl or phenyl; (c) n is 2, 3, or 4; (d) W is O; (e) Y is anunsubstituted or substituted phenylene; wherein one or more substituentsis selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy,C1-C4 haloalkyl and C1-C4 haloalkoxy; (f) R3 is a C1-C4 alkyl or C1-C4haloalkyl; (g) R4 is a substituted or unsubstituted phenyl, wherein oneor more substituents are selected from the group consisting of: halo,carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy,nitro, cyano, CHO, hydroxyl, C1-C4 alkanoic acid and —C(O)NR13R13; andwherein each R13 is independently H or a C1-C4 alkyl; and (h) R5 is H,C1-C4 alkyl, or aminoalkyl.
 2. A compound of claim 1 wherein n is
 2. 3.A compound of claim 1 wherein Y is phenylene.
 4. A compound of claim 1wherein R2 and R3 are each methyl.
 5. A compound of claim 1 wherein R4is unsubstituted phenyl.
 6. A compound of claim 1 wherein R5 is H.
 7. Acompound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: (a) R1 is anunsubstituted or substituted thiophenyl, or thiophenyl-C1-C4 alkyl;wherein one or more substituents for thiophenyl or thiophenyl-C1-C4 areselected from the group consisting of: halo, carboxyl, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, cyano, CHO,hydroxyl, C1-C4 alkanoic acid and —C(O)NR13R13; and wherein each R13 isindependently H or a C1-C4 alkyl, (b) R2 is H, C1-C4 alkyl, C1-C4haloalkyl or phenyl; (c) R5 is H, C1-C4 alkyl, or aminoalkyl; (d) R6 areeach, independently, H, C1-C4 alkyl or C1-C4 alkoxy; (e) R7 are each,independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl orphenyl; (f) R8 are each, independently, H, halo, C1-C4 alkyl, C1-C4alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8cycloalkyl, thienyl, or phenyl; and (g) R9 is C1-C4 alkyl or C1-C4haloalkyl.
 8. A compound of claim 7 wherein R2 and R9 are each methyl.9. A compound of claim 7 wherein each R6 is H.
 10. A compound of claim 7wherein R5 is H.
 11. A compound represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof, wherein: (a) R5 is H,C1-C4 alkyl, or aminoalkyl; (b) R6 are each, independently, H, C1-C4alkyl or C1-C4 alkoxy; (c) R7 are each, independently, H, halo, C1-C4alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro,methanesulfonyl, C3-C8 cycloalkyl, thienyl or phenyl; (d) R8 are each,independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, rhienyl, orphenyl; and (e) R¹⁰ is an unsubstituted or substituted , 2-thienyl, or3-thienyl, wherein one or more substituent is selected from the groupconsisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4haloalkoxy.
 12. A compound of claim 11 wherein R5 is H.
 13. A compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: (a) R7 are each,independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl orphenyl; (b) R8 are each, independently, H, halo, C1-C4 alkyl, C1-C4alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8cycloalkyl, thienyl, or phenyl; and (c) R11 is H, C1-C4 alkyl or halo.14. A compound of claim 13, wherein the compound is2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxypropionicacid.
 15. A compound of claim 14, wherein the compound is(S)-2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxypropionicacid.
 16. A compound of claim 1, wherein the compound is2-(2-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid.
 17. A compound of claim 1, wherein the compound is2-Methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-o-tolyloxy-propionicacid.
 18. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and one or more compound of claim 1, or apharmaceutically acceptable salt thereof.
 19. A method of treatingdiabetes mellitus in a mammal, comprising the step of administering tothe mammal a therapeutically effective amount of a compound of claim 1,a pharmaceutically acceptable salt thereof.
 20. The method of claim 19wherein the mammal is a human.